Greetings, Pioneers of GPCR Science! Embark on this week’s thrilling updates in GPCR research, learning opportunities, and industry developments. Don’t just stay informed—immerse yourself, expand your knowledge, and become a trailblazer in the field! This Week’s Highlights: Celebrating Excellence: Wessel A. C. Burger , Arthur Christopoulos , David M. Thal , et al., for their groundbreaking work on Positive allosteric modulation of a GPCR ternary complex Unlock Your Learning: Limited Spots Available! There are only 5 spots left for our upcoming courses, so seize the chance to learn from the best in the field. 🚨 Hurry to reserve your spot for the Principles of Pharmacology I & II BUNDLE before the Early Bird Deadline on September 27 . With just one week left, becoming a premium member is all it takes to benefit from this discount! Not a premium member yet?  No worries – you can sign up for a 5-day FREE trial! Gain access to over 500 minutes of recorded classes in our  GPCR courses   taught by Drs. Terry Kenakin  and Sam Hoare ! Every Thursday at 10 AM EST: Principles of Pharmacology I Dates: October 3, 10, 17, 24 (four sessions) Topics: Pharmacologic activity measurement, mechanisms of action, and GPCR discovery strategies. Registration deadline: September 27, 2024 Principles of Pharmacology II Dates: October 31, November 7, 14, 21, December 5 (five sessions) (we skipped Thanksgiving, of course!) Topics: New cellular assays, real-time kinetics, and unique GPCR behaviors. Registration deadline: October 25, 2024 🔥 Why You Should Enroll Now: Cost-effective & Distinctive Educational Experience Affordable courses that maintain high-quality standards. Adaptable Learning Access recorded sessions at your convenience to enhance your understanding. Our Students Highly Recommend Us! Previous students praise the course content and our exceptional service. Join us for an exciting discussion with Dr. Terry Kenakin to gain insights and prepare for upcoming courses. Don't miss this valuable opportunity! Exclusive Deal for Scientists Residing and Working in Developing Nations If you live and work  in a developing country, please complete this form to enjoy complimentary access to Dr. Kenakin's upcoming courses. Our goal is to ensure that education is within reach for everyone! Secure your spot today and dive into the evolving world of GPCRs! GPCR Event Spotlight Discovery on Target’s 19th Annual GPCR-Based Drug Discovery Targeting G Protein-Coupled Receptors for New Therapeutic Options 📍  Boston, MA 📅 October 2 -3, 2024 Join leading scientists to investigate the most recent advancements in GPCR-targeted drug development, incorporating machine learning, innovative biophysical methods, and medicinal chemistry. Register today for the GPCR Drug Discovery Conference and save $200 with discount code “ DRGPCR24 ”. 11th Adhesion GPCR Workshop    📍  Mexico City 📅 October 23-25, 2024 Engage with your peers and delve into the latest developments in adhesion GPCR biology. The full agenda is now available; check it here ! If you want to enhance your brand, email Hello@DrGPCR.com  for sponsorship opportunities. Classified GPCR News  Let’s dive into the   Classified GPCR News from September 9th to 15th, 2024 Industry News MBX aims for $136M IPO to take potential rival to Ascendis' Yorvipath into phase 3 Certa Therapeutics Announces International Non-Proprietary Name for its First-in-class GPR68 Inhibitor Asengeprast (FT011) AlphaProteo generates novel proteins for biology and health research Innovate UK announced the winners of its Transforming Cancer Therapeutics grant, which focuses on developing life-changing cancer treatments. 𝗦𝘂𝗺𝗺𝗮𝗿𝘆 𝗼𝗳 𝘁𝗵𝗲 𝗿𝗲𝘀𝘂𝗹𝘁𝘀 𝗼𝗳 𝗔𝗘𝗙𝟬𝟭𝟭𝟳 𝗣𝗵𝗮𝘀𝗲 𝟮𝗯 𝗶𝗻 𝗖𝗨𝗗 Nxera Pharma’s Partner Centessa Announces Positive Interim Phase 1 Clinical Data with its Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely Sleep-Deprived Healthy Volunteers Cumulus raising $50M, spinning GPR68 small molecules into GIO New treatments being developed for schizophrenia Crinetics Pharmaceuticals Announces September 2024 Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Call for GPCR Papers Deadline: Nov 1, 2024. Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery September 22, 2024 | Biomolecular Horizons 2024 September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   NEW November 25 - 27, 2024 | 1st Virtual GPCR Forum Conference November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs HIGHLIGHT Research Associate - Professor Graeme Milligan HIGHLIGHT Postdoc in Molecular Pharmacology - The Hauser Group NEW Postdoctoral Scholar – iPSC in cardiac and endothelial cell function NEW Protein Biochemist/Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Adhesion GPCRs Loss of cardiomyocyte-specific Adhesion G Protein Coupled Receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure GPCR Activation and Signaling Positive allosteric modulation of a GPCR ternary complex GPCR Binders, Drugs, and more Progress on the development of Class A GPCR-biased ligands GPCRs in Cardiology, Endocrinology, and Taste CRTC1 in Mc4r-expressing cells is required for peripheral metabolism and systemic energy homeostasis Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis GPCRs in Neuroscience Gain control of sensory input across polysynaptic circuitries in mouse visual cortex by a single G protein-coupled receptor type (5-HT2A) GPCRs in Oncology and Immunology The power of many: Multilevel targeting of representative chemokine and metabolite GPCRs in personalized cancer therapy GPR97 depletion aggravates imiquimod-induced psoriasis pathogenesis via amplifying IL-23/IL-17 axis signal pathway Structural and Molecular Insights into GPCR Function Exploring the constitutive activation mechanism of the class A orphan GPR20 Become a Premium Member! 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Hello GPCR Enthusiasts, Dive into this week's exciting updates on cutting-edge GPCR research, new learning opportunities, and industry news! Don't miss out—explore, learn, and elevate your expertise today! Weekly Highlights: Congrats to: Daniel Matúš , Simone Prömel , et al., for their work on The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans Alexei Sirbu , Paolo Annibale , et al., for their study on Cell swelling enhances ligand-driven β-adrenergic signaling ✨ Reserve Your seat before these fill up! Our updated course schedule is designed to fit seamlessly into your routine, offering an enriched learning experience. Every Thursday at 10 AM EST: Principles of Pharmacology I October 3, 10, 17, 24 (four sessions) Topics: Pharmacologic activity measurement, mechanisms of action, and GPCR discovery strategies. Principles of Pharmacology II October 31, November 7, 14, 21, December 5 (five sessions) (we skipped Thanksgiving, of course!) Topics: New cellular assays, real-time kinetics, and unique GPCR behaviors. 🔥 Why You Should Enroll Now: Act Fast & Save Big! The Principles of Pharmacology I & II BUNDLE is your key to mastering the field. You can embrace a  25% OFF early bird discount as a premium member . But act fast – this offer is only available for a limited time. Not a premium member yet? No problem – we offer a 5-day FREE trial! And access over 500 minutes of recorded classes in our  GPCR courses with Drs. Terry Kenakin and Sam Hoare ! Affordable & Unique Learning Experience Our budget-friendly courses offer a unique approach to mastering pharmacology. Flexible Learning Rewatch sessions anytime to reinforce your learning. Our Students Love Us! Past students rave about the content and service of our courses. Join us for an exciting discussion with Dr. Terry Kenakin as he shares insights into what you can anticipate for the upcoming courses. Don't miss this fantastic opportunity to gain valuable knowledge and prepare for the forthcoming sessions! Exclusive Deal for Scientists Residing and Working in Developing Nations If you live and work  in a developing country, please complete this form to enjoy complimentary access to Dr. Kenakin's upcoming courses. Our goal is to ensure that education is within reach for everyone! Secure your spot today and dive into the evolving world of GPCRs! GPCR Event Spotlight Discovery on Target’s 19th Annual GPCR-Based Drug Discovery Targeting G Protein-Coupled Receptors for New Therapeutic Options 📍  Boston, MA 📅 October 2 -3, 2024 Join top researchers to explore the latest in GPCR-targeted drug design, including machine learning, new biophysical techniques, and medicinal chemistry. Register today for the GPCR Drug Discovery Conference and save $200 with discount code “ DRGPCR24 ”. 11th Adhesion GPCR Workshop    📍  Mexico City 📅 October 23-25, 2024 Connect with your colleagues and immerse yourself in the most recent advancements in adhesion GPCR biology. Stay tuned for the release of the full agenda! Are you interested in boosting your brand? Contact us at Hello@DrGPCR.com  for sponsorship opportunities. Classified GPCR News  Let’s dive into the   Classified GPCR News from September 2nd to 8th, 2024 Industry News Superluminal Medicines Closes $120 Million Series A Round Domain Therapeutics has been nominated for Prix Galien USA Carterra unveils its most sensitive biosensor platform; Carterra Ultra™ ushers in a new frontier in fragment and small molecule drug discovery Is the pharma community looking hard enough before trying to engage highly challenging neurology targets? Engaging multiple sclerosis by drugging a “simple” GPCR. This technique for studying cell receptors could have sweeping implications for drug development DeepCure team is excited to welcome Justin Potnick, to our Medicinal Chemistry group Call for GPCR Papers Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery NEW September 22, 2024 | Biomolecular Horizons 2024 September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   NEW November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs HIGHLIGHT Research Associate - Professor Graeme Milligan HIGHLIGHT Postdoc in Molecular Pharmacology - The Hauser Group Senior Scientist/Staff Scientist, Computational Chemistry Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Adhesion GPCRs The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH Signaling GPCR Activation and Signaling Illuminating GPCR trafficking Cell swelling enhances ligand-driven β-adrenergic signaling Roles of the gate loop in β-arrestin-1 conformational dynamics and phosphorylated receptor interaction Early Events in β2AR Dimer Dynamics Mediated by Activation-Related Microswitches Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: Possible mechanisms involved An engineered trafficking biosensor reveals a role for DNAJC13 in DOR downregulation GPCRs in Cardiology, Endocrinology, and Taste Role of G protein coupled receptors in acute kidney injury Ligand-Dependent and G Protein-Dependent Properties for the Sweet Taste Heterodimer, TAS1R2/1R3 GPCRs in Neuroscience GPCR-Mediated Natural Products and Compounds: Potential Therapeutic Targets for the Treatment of Neurological Disease s Activation of GPR55 alleviates neuropathic pain and chronic inflammation Developmental exposures to common environmental pollutants result in long-term Reprogramming of hypothalamic-pituitary axis in mice GPCRs in Oncology and Immunology A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages Structural and Molecular Insights into GPCR Function Insights into the structure and activation mechanism of some class B1 GPCR family members Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation Become a Premium Member! 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Significant advancements in the cellular biology of G protein-coupled receptors (GPCRs) about a novel biosensor shed light on the endosomal proteome associated with the δ-opioid receptor (DOR). This study, published in Nature Chemical Biology, highlights the role of the chaperone protein DNAJC13 in the endosomal-lysosomal pathway for DOR. The research team, led by Brandon Novy and colleagues, utilized an innovative APEX2/AUR biosensor that allows scientists to monitor the agonist-induced trafficking of DOR to the lysosome with high precision. By employing this biosensor, the research team identified 492 genes that significantly influence DOR function, with DNAJC13 emerging as a standout candidate along with WDR91 and SNX24. The findings suggest that DNAJC13 is crucial to the trafficking of DOR, facilitating its downregulation and influencing cellular signaling pathways essential for pain and anxiety regulation. How does this new biosensor work? The critical player is Apurinic/Apyrimidinic Endodeoxyribonuclease 2 (APEX2). APEX2 is a peroxidase enzyme that catalyzes the oxidation of specific substrates in the presence of hydrogen peroxide (H 2 O 2 ). Therefore, it’s a great molecular tool for proximity labeling approaches in living cells.  In this study, the DOR receptor was genetically fused to APEX2, creating a DOR-APEX2 construct. Upon agonist activation, the DOR-APEX2 complex is internalized and trafficked to the lysosome. During this process, APEX2 can label proteins in the vicinity, allowing the capture of a snapshot of the endosomal proteome associated with the DOR receptor. APEX2 biosensor utilizes a fluorogenic substrate called Amplex UltraRed (AUR). When AUR is oxidized by APEX2 in the presence of H 2 O 2 , it produces a fluorescent product that can be detected and quantified. This fluorescence serves as a readout for the activity of APEX2 and, by extension, the trafficking of the GPCR of interest. After the labeling reaction, the researchers purified and biotinylated proteins (those that have been labeled by APEX2) and analyzed them using quantitative proteomics such as tandem mass tags. Finally, this analysis provided insights into the molecular composition of the endosomal environment and the proteins involved in the trafficking of the DORs. The development of molecular tools to study GPCR trafficking in real-time opens new avenues for understanding drug tolerance and resistance, particularly in the context of opioid therapies. As the opioid crisis continues to challenge public health, insights gained from this research could inform the development of safer analgesics that minimize the risk of addiction while maintaining their efficacy. The implications of this research extend beyond basic science ; understanding the role of DNAJC13 in GPCR trafficking could profoundly affect the development of therapeutic strategies for conditions related to other GPCR-mediated pathways. As the field continues to evolve, this study represents a crucial step toward unraveling the understanding of GPCR regulation and its potential to revolutionize human health. For further details, refer to the full article: DOI: 10.1038/s41589-024-01705-2

Hello GPCR Community, Stay up-to-date with the latest GPCR research, including breakthrough studies, upcoming events, and our newly announced pharmacology courses. Don't miss exclusive discounts, expert insights, and opportunities to elevate your learning with our tailored programs. Secure your spot today and dive into the evolving world of GPCRs! This week's highlights include congrats to: Bruce Allen , Terence Hébert , et al. for their work on Understanding the impact of nuclear-localized GPCRs on cellular signaling. Lukas Grätz , Jan Voss , and Gunnar Schulte , for their study on Class-Wide Analysis of Frizzled-Dishevelled Interactions Using BRET Biosensors Reveals Functional Differences among Receptor Paralogs . Małgorzata Kogut-Günthel , Antonella Di Pizio , et al. for their research on The path to the G protein-coupled receptor structural landscape: Major milestones and future directions . 🎉 New Course Dates Announced: Don’t Miss Out! Our refreshed schedule is designed to fit seamlessly into your calendar and enhance your learning experience. Every Thursday at 10 AM EST: Principles of Pharmacology I October 3, 10, 17, 24 (four sessions) Explore pharmacologic activity measurement, mechanisms of action, and GPCR discovery strategies. Principles of Pharmacology II October 31, November 7, 14, 21, December 5 (five sessions) (we skipped Thanksgiving, of course!) Delve into new cellular assays, real-time kinetics, and unique GPCR behaviors. 🔥 Why You Should Enroll Now: Act Fast & Save Big! The Principles of Pharmacology I & II BUNDLE is your golden ticket to mastering the field. Premium members can enjoy a 25% OFF early bird discount , but hurry - it's only available for a limited time. Not a premium member yet? Don't worry - we offer a 5-day FREE trial! Plus, access to over 500 minutes of recorded classes of our GPCR Courses with Drs. Terry Kenakin and Sam Hoare ! Affordable & Unique Learning Experience Dive deep into pharmacology with our budget-friendly courses that offer a unique approach to understanding the field. Rewatch Anytime Enjoy the flexibility of rewatching sessions at your convenience to reinforce your learning. Don't miss out on our fantastic discussion with Dr. Terry Kenakin on what to anticipate for these courses! Special Offer for Scientists who work and live in developing countries If you live and work in a developing country, please fill out this form to receive complimentary access to Dr. Kenakin's upcoming classes. We’re committed to making education accessible to all! Secure your spot today and elevate your pharmacology expertise! Don’t miss this chance to benefit from our early bird pricing and premium content. GPCR Event Spotlight Discovery on Target’s 19th Annual GPCR-Based Drug Discovery Targeting G Protein-Coupled Receptors for New Therapeutic Options 📍  Boston, MA 📅 October 2 -3, 2024 GPCRs, among the most ancient and complex drug targets, remain central in modern targeted drug discovery. The 19th Annual GPCR-Based Drug Discovery conference (October 2-3, 2024, in Boston and online) gathers top researchers to explore the latest advances in designing precise GPCR-targeted drugs, including the role of machine learning, new biophysical techniques, and medicinal chemistry approaches in understanding these challenging receptors. Join us October 2-3 at the GPCR Drug Discovery Conference . Register today and save $200 off the current rate. Use discount code “ DRGPCR24 ” to save. 11th Adhesion GPCR Workshop    📍  Mexico City 📅 October 23-25, 2024 Join us to connect with peers and explore the latest in adhesion GPCR biology. Full Agenda Coming Soon! Are you interested in boosting your brand? Contact us at Hello@DrGPCR.com  for sponsorship opportunities. Classified GPCR News  Let’s dive into the   Classified GPCR News from August 26th to September 1st, 2024 Industry News GPCR-RAMP Interactome Maps Could Help Drug Developers Find Buried Treasures Edelris Announces Research Services Agreement with Pfizer on Targeted Protein Degradation Modalities A quick revision of how β-adrenergic receptors work and how their antagonists can achieve therapeutic outcomes. Domain Nominated for Prestigious Prix Galien USA ‘Best Startup’ Award: Pioneering GPCR-Driven Immunotherapies in Cancer Treatment Structure Therapeutics Appoints Angus C. Russell to Board of Directors Adiso Announces Groundbreaking Research Highlighting ADS024 a Novel Oral Agent for Neuroinflammation Call for GPCR Papers Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs HIGHLIGHT Research Associate - Professor Graeme Milligan NEW   Postdoc in Molecular Pharmacology - The Hauser Group NEW Senior Scientist/Staff Scientist, Computational Chemistry Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   GPCR Activation and Signaling Profiling the proximal proteome of the activated μ-opioid receptor Understanding the impact of nuclear-localized GPCRs on cellular signalling GRK2 is critical for the cleavage of the porcine embryo by regulating HSP90 and the AKT pathway Structural basis for CCR6 modulation by allosteric antagonists Class-Wide Analysis of Frizzled-Dishevelled Interactions Using BRET Biosensors Reveals Functional Differences among Receptor Paralogs GPCRs in Neuroscience Opposing GPCR signaling programs protein intake setpoint in Drosophila Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression GPCRs in Oncology and Immunology Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma Identification of Small-Molecule Antagonists Targeting the Growth Hormone Releasing Hormone Receptor (GHRHR) Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes Methods & Updates in GPCR Research A nondestructive membrane engineering method using an amphiphilic polymer Labeling of CC Chemokine Receptor 2 with a Versatile Intracellular Allosteric Probe Selective optogenetic inhibition of Gαq or Gαi signaling by minimal RGS domains disrupts circuit functionality and circuit formation Reviews, GPCRs, and more G Protein-Coupled Receptors in Skin Aging The path to the G protein-coupled receptor structural landscape: Major milestones and future directions Going rogue: mechanisms, regulation, and roles of mutationally activated Gα in human cancer Structural and Molecular Insights into GPCR Function Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5 Altered O-glycosylation of β1-adrenergic receptor N-terminal single-nucleotide variants modulates receptor processing and functional activity Differential pathogenetic mechanisms of mutations in helix 2 and helix 6 of rhodopsin Become a Premium Member! 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“ A substitution of one amino acid by another in a protein can have effects ranging from negligible to dramatic, either locally or distantly .” (Bikker et al., 1998) Quantitative studies of how drugs modulate their targets have been instrumental in discovering new treatments. A rational drug discovery campaign hinges on a deep understanding of how distinct molecules interact with receptors at the molecular level. Fortunately, several techniques and methodologies have been developed to support this process. Notably, innovations in structural biology, such as X-ray crystallography and cryo-electron microscopy, have successfully elucidated ligand-receptor interactions. For example, Carlsson et al. (2010) utilised structural information and virtual ligand screening to discover novel ligands for the A 2A  adenosine receptor. While these structural techniques offer significant advantages in drug discovery, no single method can fully capture the impact of residue alterations on ligand function and ligand-receptor interactions. But why is this information crucial?  Kosar et al. (2024) addressed this question by using the role of the Trp258 6.48 residue to guide and explain the discovery of a novel inverse agonist at the cannabinoid receptor 2. Furthermore, data on the role of specific residues within receptors can provide valuable insights for structure-activity relationship (SAR) studies, informing the development of ligands tailored to exploit available binding pocket space. In this context, mutagenesis has emerged as an "old-school" but essential technology to fill these knowledge gaps. Mutagenesis involves deliberately altering the DNA sequence of a gene to study the resulting changes in protein function. Through either random or targeted (site-directed) approaches, mutagenesis can provide a comprehensive understanding of how drugs interact with different receptor regions and link these interactions to functional variations. This technique has uncovered fundamental aspects of the G protein-coupled receptor (GPCR) function, including specific ligand interactions, such as those at the adenosine A 1  adenosine receptor (Nguyen et al., 2016). While advancements in site-directed technology have largely supplanted random mutagenesis, the latter has seen a resurgence in recent times for exploratory analyses to identify previously unknown regions critical to GPCR function. For example, random mutagenesis, combined with novel specificity high-throughput selection, has been used to identify specificity-determining positions without prior knowledge of structure or sequence homology (Di Roberto et al., 2017). However, several challenges have limited the use of mutagenesis in drug discovery. Targeted mutagenesis may miss broader functional regions, while random mutagenesis generates extensive data that require labour-intensive screening. Furthermore, probing species- or subtype-selectivity introduces complexities due to the differing contexts of receptor subtypes across species. Integrating mutagenesis data with computational models also presents challenges, requiring high-quality data and robust algorithms. Moreover, these studies are resource-intensive, necessitating significant investments in technology and infrastructure. To overcome these challenges, future directions include developing high-throughput techniques, better integrating experimental and computational methods, and improving frameworks for data interpretation. Advances in bioinformatics and machine learning will play a pivotal role in addressing these obstacles, enhancing our understanding of GPCR structure and function. For instance, Heydenreich et al. (2023) developed a data science framework that combined mutagenesis and structural data to contextualise ligand-induced structural changes and reveal the principles underlying efficacy and potency. Additionally, deep mutational scanning can generate large-scale datasets, allowing researchers to determine the functional consequences of every possible amino acid change at each position in a protein, as well as the biochemical activity of hundreds of thousands of protein variants (Fowler and Fields, 2014). In summary, mutagenesis can be a critical tool in drug discovery, particularly for studying GPCRs. While advancements in structural biology techniques like X-ray crystallography and cryo-electron microscopy have deepened our understanding of ligand-receptor interactions, mutagenesis fills crucial knowledge gaps by revealing how specific amino acid changes impact receptor function. Despite its significant contributions, challenges such as data complexity, resource intensity, and integration with computational models remain. Future advancements, including high-throughput techniques and bioinformatics integration, will further enhance the utility of mutagenesis in drug discovery. Reference   Bikker, J. A., Trumpp-Kallmeyer, S., & Humblet, C. (1998). G-protein coupled receptors: models, mutagenesis, and drug design. Journal of Medicinal Chemistry , 41 (16), 2911-2927. Carlsson, J., Yoo, L., Gao, Z. G., Irwin, J. J., Shoichet, B. K., & Jacobson, K. A. (2010). Structure-based discovery of A2A adenosine receptor ligands. Journal of Medicinal Chemistry , 53 (9), 3748-3755. Di Roberto, R. B., Chang, B., & Peisajovich, S. G. (2017). The directed evolution of ligand specificity in a GPCR and the unequal contributions of efficacy and affinity. Scientific Reports , 7 (1), 16012. Fowler, D. M., & Fields, S. (2014). Deep mutational scanning: a new style of protein science. Nature Methods , 11 (8), 801-807. Heydenreich, F. M., Marti-Solano, M., Sandhu, M., Kobilka, B. K., Bouvier, M., & Babu, M. M. (2023). Molecular determinants of ligand efficacy and potency in GPCR signaling. Science , 382 (6677), eadh1859. Kosar, M., Sarott, R. C., Sykes, D. A., Viray, A. E., Vitale, R. M., Tomašević, N., ... & Carreira, E. M. (2024). Flipping the GPCR switch: Structure-based development of selective cannabinoid receptor 2 inverse agonists. ACS Central Science , 10 (5), 956-968. Nguyen, A. T., Baltos, J.-A., Thomas, T., Nguyen, T. D., Muñoz, L. L., Gregory, K. J., White, P. J., Sexton, P. M., Christopoulos, A., & May, L. T. (2016). Extracellular loop 2 of the adenosine A1 receptor has a key role in orthosteric ligand affinity and agonist efficacy. Molecular Pharmacology ,  90 (6), 703-714.

Dear GPCR Enthusiasts , Get ready for an exciting learning experience with our newly updated Principles of Pharmacology I & II  courses! We've refreshed the schedule and can’t wait for you to join us on these new dates. New Course Dates: Principles of Pharmacology I :  October 3, 10, 17, 24 (four sessions) Principles of Pharmacology II :  October 31, November 7, 14, 21, December 5 (five sessions) Courses Highlights Act Fast: Don’t miss this incredible opportunity to immerse yourself in the  Principles of Pharmacology I & II BUNDLE . Grab this chance to deepen your understanding of pharmacology and take your knowledge to the next level! Secure your spot today and elevate your expertise! Premium members enjoy a 5-day free trial—join now and save with the 25% OFF early bird discount . Enrollment is now open to the public! Topics include pharmacologic activity measurement, mechanisms of action, and GPCR discovery strategies. Take advantage of a 25% early bird discount for premium members! Topics cover new cellular assays, real-time kinetics, and unique GPCR behaviors. Secure your spot now by signing up today! Did you know...? As a  premium member , you can access over 500 minutes of exclusive, expert-led content from esteemed leaders, Drs. Kenakin and Hoare . We highly recommend exploring valuable resources such as ' Applying Pharmacology to Drug Discovery ' and ' Advanced Data Analysis for GPCR Pharmacology' ." GPCR Event Spotlight    11th Adhesion GPCR Workshop    Location:  Mexico City Dates:  October 23-25, 2024 Connect with peers and delve into cutting-edge adhesion GPCR biology. Interested in boosting your brand? Reach out to us at Hello@DrGPCR.com for sponsorship opportunities .  Let’s dive into the   Classified GPCR News  from August 19th to 25th, 2024 GPCR Activation and Signaling Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling GPCR Binders, Drugs, and more Selenomethionine Promotes Milk Protein and Fat Synthesis and Proliferation of Mammary Epithelial Cells through the GPR37-mTOR-S6K1 Signaling GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related behaviors in Sapap3 knockout mice Methods & Updates in GPCR Research Genome-wide identification of 769 G protein-coupled receptor (GPCR) genes from the marine medaka Oryzias melastigma Industry News Cumulus Oncology and leadXpro Achieve Critical Milestone in GPR68 Drug Discovery Project Ambrosia lands $16m to ‘improve on existing GLP-1 drugs’ Opening Ceremony of Xuzhou Zhongshu Research Site and CNS Drug Innovation Forum Nxera Pharma Notes Positive Phase 2 Data for Partnered Schizophrenia Candidate NBI-1117568 Call for GPCR Papers NEW Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery NEW September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs NEW Research Associate Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   Become a Premium Member! Get your 5-day free trial TODAY!

Dear GPCR Community, Before diving into this week's news, prepare for an incredible learning journey! We’ve made some updates to the Principles of Pharmacology I & II courses, and we can’t wait for you to join us on these new dates. Here’s the refreshed schedule: Principles of Pharmacology I October 3, 10, 17, 24 Principles of Pharmacology II October 31 November 7, 14, 21 December 5 As a premium member , you’re also unlocking over 500 minutes of exclusive, expert-led content from thought leaders like Drs. Kenakin and Hoare. Don’t miss out on insightful resources like '   Applying Pharmacology to Drug Discovery ' and ' Advanced Data Analysis for GPCR Pharmacology .' We’re thrilled to have you with us on this learning journey! Courses Highlights The clock is ticking!  Don’t miss your chance to dive into the Principles of Pharmacology I & II BUNDLE . Grab your spot today and score a 25% early bird discount—exclusively for premium members. Register now and level up your expertise! Become a premium member today and enjoy a 5-day free trial. Enrollment:  Open to the Public Now! Dates:  October 3 to 24, 2024 (four sessions) Topics:  Measuring pharmacologic activity, mechanisms of action, and GPCR discovery strategies. Discount:  25% off for Premium Members—Act Fast! Dates:  October 31, November 7 - 14 -21, and December 5, 2024 (five sessions) Topics:  New cellular assays, real-time kinetics, and discovering unique GPCR behaviors. Sign up today to secure your spot! GPCR Event Spotlight    11th Adhesion GPCR Workshop    Location:  Mexico City Dates:  October 23-25, 2024 Join us  to connect with peers and explore cutting-edge adhesion GPCR biology. Don't miss the chance to boost your brand's presence at this exclusive event. Contact us at Hello@DrGPCR.com  to discover exciting sponsorship opportunities . This week's highlight includes congrats to: Madison Walker , Benjamin Myers , et al., for their research on GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade Elita Yuliantie , Arthur Christopoulos , Patrick M. Sexton , Denise Wootten , et al., for their work on Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs  Let’s dive into the   Classified GPCR News  from August 12th to 18th, 2024 Adhesion GPCRs Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors GPCR Activation and Signaling A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade Allatotropin (AT) related peptides L-ATRP and D2-ATRP diastereomers activate an endogenous receptor and suppress heart rate in the Pacific abalone Haliotis discus hannai GPCR Binders, Drugs, and more Photo-BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs GPCRs in Cardiology, Endocrinology, and Taste Regulator of G-protein signaling expression in human intestinal enteroendocrine cells and potential role in satiety hormone secretion in health and obesity GPCRs in Neuroscience Light and dopamine impact two circadian neurons to promote morning wakefulness LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties GPCRs in Oncology and Immunology Chemoattractant receptor signaling in humoral immunity Methods & Updates in GPCR Research Probing PAC1 receptor activation across species with an engineered sensor A Multi-Angle Approach to Predict Peptide-GPCR Complexes: The N/OFQ-NOP System as a Successful AlphaFold Application Case Study Constitutive and Conditional Epitope Tagging of Endogenous G-Protein-Coupled Receptors in Drosophila Measuring G protein activation by spectrally resolved imaging fluorescence fluctuation spectroscopy Structural and Molecular Insights into GPCR Function Monitoring GPCR conformation with GFP-inspired dyes Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor Structural analysis of the human C5a-C5aR1 complex using cryo-electron microscopy Structural analysis of the human C5a-C5aR1 complex using cryo-electron microscopy Industry News Crinetics Pharmaceuticals Announces August 2024 Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Unlocking New Possibilities in GLP-1R Drug Discovery GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Become a Premium Member! Get your 5-day free trial TODAY!

Dear GPCR Enthusiasts! Get ready to save the dates! Dr. GPCR University offers two live courses this fall that you won’t want to miss. Before the new semester kicks off, dive into our premium on-demand courses! With your membership, you’ll access over 500 minutes of top-notch content from Drs. Kenakin and Hoare on '   Applying Pharmacology to Drug Discovery ' and ' Advanced Data Analysis for GPCR Pharmacology .' Choose between our monthly or yearly plans (with a 5-day free trial) to enjoy these courses and snag 25% off early bird discounts on upcoming classes. Check out what’s coming in September and October: Sign up for both courses now and score a 25% early bird discount with a premium membership! Course Details: When:  Thursdays at 10 AM EST Format:  Engaging Online Lectures with access to pre-read materials. Perks Include: In-depth Reading Materials Access to a Private Community Certificate of Participation for each course Don’t miss out—grab this special offer today! s Check out the details of each course below: Open to the Public: Enrollment is Now Available! Hurry and secure your spot TODAY! Dates:  September 5 to 26, 2024 What You’ll Learn during the four sessions: How to measure pharmacologic activity of ligands (affinity, efficacy, co-operativity) Determining mechanisms of action for new GPCR ligands Key elements of a comprehensive and effective GPCR discovery strategy Exclusive 25% Early Bird Discount for Dr. GPCR Ecosysme Premium members. Secure your spot before public enrollment opens! Dates:  October 3 to 31, 2024 What You’ll Master during the five sessions: Utilizing new cellular assays to analyze GPCR ligand behavior Predicting activity and in vivo target coverage with real-time kinetics Discovering new ligands and unique GPCR behaviors for innovative drug profiles GPCR Event Highlight  11th Adhesion GPCR Workshop    Location : Mexico City Dates : October 23-25, 2024 Join us in the vibrant heart of Mexico City to connect with fellow scientists and delve into the latest advances in adhesion GPCR biology. Logo Contest : Let your creativity shine! Submit your design for our Logo Contest by August 15, 2024 (Yes, it's TODAY)! Sponsorship Opportunities : Elevate your brand’s visibility at this prestigious event. Contact us at Hello@DrGPCR.com to explore sponsorship options. Your participation is eagerly awaited! This week's highlight includes congrats to: Miles Thompson ,   Alexander Hauser ,   Caroline Gorvin ,   et al.   for their work on GPCR pharmacogenomics  Let’s dive into the   Classified GPCR News  from August 5th to 11th, 2024 GPCR Activation and Signaling Pharmacological characterization of the zebrafish Hrh2a histamine H2 receptor Revealing the graded activation mechanism of neurotensin receptor 1 Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP Olanzapine manipulates neuroactive signals and may onset metabolic disturbances GPCR Binders, Drugs, and more Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of β2-adrenergic receptors GPCRs in Neuroscience In-silico predicted mouse melanopsins with blue spectral shifts deliver efficient subcellular signaling Striatal serotonin release signals reward value Ciliary length variations impact cilia-mediated signaling and biological responses The receptor tyrosine kinase IGF1R and its associated GPCRs are co-regulated by the noncoding RNA NEAT1 in Alzheimer's disease Nanoplastic at environmentally relevant concentrations induces toxicity across multiple generations associated with inhibition in germline G protein-coupled receptor CED-1 in Caenorhabditis elegans Calcium-sensing receptor regulates Kv7 channels via Gi/o protein signalling and modulates excitability of human induced pluripotent stem cell-derived nociceptive-like neurons Methods & Updates in GPCR Research G protein-coupled receptor (GPCR) pharmacogenomics Visualization of endogenous G proteins on endosomes and other organelles Reviews, GPCRs, and more Phytocannabinoids in neuromodulation: From omics to epigenetics The impact of nanobodies on GPCR structural biology and their potential as therapeutic agents Industry News Nxera Pharma Operational Highlights and Consolidated Results for the Second Quarter and First Half 2024 Cracking Codes in Cellular Communication Neurocrine Biosciences to Present at the Canaccord Genuity 44th Annual Growth Conference GPCR drugs make up a third of the market! GPCRs and mRNA antigens enable drug discovery and development Mapping GPCR-RAMP complexes with MolBoolean Screening GPR75 Modulators Using Medium-Throughput Reporter Gene Assay GPCR Therapeutics Optimizes the Joint Development of New Drugs Using Intralinks’ Virtual Data Room   GPCR Events, Meetings, and Webinars NEW September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Become a Premium Member! Get your 5-day free trial TODAY!

Hey there, readers! Take a look at our GPCR coverage for this week. We've got 11 GPCR papers, seven industry news pieces, a new GPCR event, and even a job ad.   This week's highlight includes congrats to: Miles Thompson , Alexander Hauser , Caroline Gorvin ,   et al.   for their work on GPCR gene variants and human genetic disease Ilana Kotliar , Thomas Sakmar , et al. for their study on Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins Nicholas Kapolka , Geoffrey Taghon , and Daniel Isom  for their research on Advances in yeast synthetic biology for human GPCR biology and pharmacology Dr. GPCR University Early-Bird Registration Open for Premium Members! Unlock a 25% exclusive discount on these courses with Dr. Terry Kenakin with our premium membership and enjoy a 1-month FREE trial! Don’t miss out—secure your spot today! Registrations for the public will be on Monday! Hurry! Courses Schedule and  Benefits Every Thursday at 10 am EST Online Lectures 1:1 meeting with Dr. Terry Kenakin Reading Materials Access to the private group Certificate of participation Learn the essentials: Measuring the pharmacologic activity of ligands (affinity, efficacy, co-operativity) Determining mechanisms of action for new GPCR ligands Elements of a comprehensive and effective GPCR discovery Master advanced applications: Using new cellular assays to analyze GPCR ligand behavior Predicting activity and in vivo target coverage with real-time kinetics Discovering new ligands and GPCR behaviors for unique drug profiles   GPCR Event Highlight 11th Adhesion GPCR Workshop Join us in vibrant Mexico City from October 23-25, 2024, to connect with fellow scientists and explore the latest in adhesion GPCR biology. Logo Contest : Let your creativity shine by submitting your design for the Logo Contest before August 15, 2024 Sponsorship Opportunities :   Elevate your brand's presence at this scientific event . Contact us at Hello@DrGPCR.com   to learn more. Your participation is eagerly awaited!  Let’s dive into the   Classified GPCR News  from July 29th to August 4th, 2024 GPCR Activation and Signaling ONE-GO: Direct detection of context-dependent GPCR activity Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins Molecular mechanism of bitter taste receptor agonist-mediated relaxation of airway smooth muscle GPCR Binders, Drugs, and more Expanding Structure-Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N-Terminal Region for Novel Urotensin II Receptor Modulators GPCRs in Oncology and Immunology G protein-coupled receptor-mediated signaling of immunomodulation in tumor progression Methods & Updates in GPCR Research GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function Engineering a GPCR-based yeast biosensor for a highly sensitive melatonin detection from fermented beverages The calcium-binding photoprotein clytin II: Expression of the preferred human codon-optimized clytin II gene in Chinese hamster ovary-K1 cells and its use in the G-protein-coupled receptor assays Predicting the Hallucinogenic Potential of Molecules Using Artificial Intelligence Reviews, GPCRs, and more G protein-coupled receptor (GPCR) gene variants and human genetic disease Advances in yeast synthetic biology for human G protein-coupled receptor biology and pharmacology Industry News Muscarinic drugs breathe new life into schizophrenia pipeline GPCR Dynamics Reveal Mechanisms for Drug Discovery DMS: Linking Protein Structure To Function AbbVie Completes Acquisition of Cerevel Therapeutics Nxera Pharma attended the Drug Discovery Ecosystem Summit Tectonic Therapeutic Announces Closing of Merger with AVROBIO as well as Concurrent Private Placement of $130.7 Million Tectonic Therapeutic Announces US IND Clearance for Lead Program, TX45   GPCR Events, Meetings, and Webinars September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry NEW October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs NEW Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Join Dr. GPCR Ecosystem

📰 GPCR Weekly News, July 22 to 28, 2024 In the fast-paced world of pharmaceuticals and drug discovery, it is crucial for professionals to stay informed about the latest advancements and breakthroughs. We have 18 GPCR papers, four industry news articles, and two job ads. This week's highlight includes congrats to: Clementine E Philibert and Mikel Garcia-Marcos   for their work on Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators András D Tóth , Gábor Turu , and László Hunyady  for their research on Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors Antonios Drakopoulos , Peter Gmeiner , Davide Calebiro , Michael Decker , et al. for their study on Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors Dr. GPCR University Early-Bird Registration Now Open for Premium Members! We’re thrilled to announce our upcoming courses with Dr. Terry Kenakin ! Get your premium membership  and enjoy a 25% exclusive discount (1 month FREE trial!) . Don’t miss out—secure your spot today! Courses Schedule and Benefits Every Thursday at 10 am EST Online Lectures 1:1 meeting with Dr. Terry Kenakin Reading Materials Access to the private group Certificate Explore: Key metrics for assessing ligand pharmacology (affinity, efficacy, co-operativity) Mechanisms of action for new GPCR ligands Essentials for effective GPCR discovery Discover: Advanced cellular assays for GPCR ligand behavior Real-time kinetics for predicting activity Unique drug profiles from new ligands and GPCR behaviors GPCR Event Highlight Join us in vibrant Mexico City from October 23-25, 2024, for the 11th Adhesion GPCR Workshop ! Connect with fellow scientists and dive into the latest in adhesion GPCR biology. Logo Contest : Submit your design by August 15, 2024, to have your artwork featured at the event. Sponsorship Opportunities :   Boost your brand’s visibility at this scientific event. Contact us at Hello@DrGPCR.com  to learn more. We look forward to your participation! Let’s dive into the   Classified GPCR News  from July 22 to 28, 2024 GPCR Activation and Signaling Activating an invertebrate bistable opsin with the all-trans 6.11 retinal analog Comparison of the Genomic Activity of an EP4-Receptor and β2-Adrenoceptor Agonist in BEAS-2B Human Bronchial Epithelial Cells: In Search of Compartmentalized, cAMP-dependent Gene Expression Ligand bias at the muscarinic acetylcholine receptor family: opportunities and challenges Modulating Vertebrate Physiology by Genomic Fine-Tuning of GPCR Functions Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors Inverse Regulation of C-C Chemokine Receptor 3 Oligomerization by Downstream Proteins Indicates Biased Signal Transduction Pathways Activation of a GPCR, ORL1 receptor: A novel therapy to prevent heart failure progression GPCR Binders, Drugs, and more Advances in GPCR-targeted drug development in dermatology Advances in small-molecule insulin secretagogues for diabetes treatment GPCRs in Neuroscience Astrocytes control quiescent NSC reactivation via GPCR signaling-mediated F-actin remodeling GPCRs in Oncology and Immunology Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: from RNA sequencing data analysis to in vitro validation Signaling by Neutrophil G Protein-Coupled Receptors that Regulate the Release of Superoxide Anions GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression Methods & Updates in GPCR Research Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors Structural and Molecular Insights into GPCR Function Vibrational Energy Landscapes and Energy Flow in GPCRs Allosterism in the adenosine A2A and cannabinoid CB2 heteromer Mechanistic insights from the atomic-level quaternary structure of short-lived GPCR oligomers in live cells Industry News Confo Therapeutics Announces EUR 60M Series B Financing to Advance a Pipeline of Novel GPCR-Modulating Therapies into Clinical Development How To Discover Biologics For Challenging Targets Drug discovery, a biophysics perspective Bio-Rad Adds Rapid Bispecific Antibody Prototyping and Screening Services to Pioneer Antibody Discovery Platform GPCR Events, Meetings, and Webinars November 5 - 7, 2024 | 16th Annual PEGS Europe   September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs NEW Postdoctoral Position NEW Postdoctoral research position Senior or Lead Researcher   Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Senior Scientist - Discovery Biotherapeutics    Join Dr. GPCR Ecosystem

📰 GPCR Weekly News, July 15 to 21, 2024 Hey everyone! Drum rolls, we’ve got 15 GPCR research papers, updates, industry news events, and GPCR ads curated just for you!   This week's highlight includes congrats to Omolade Otun , Chris de Graaf , Cherine Bechara , et al. for their work on Conformational dynamics underlying atypical chemokine receptor 3 activation   Michael Trogdon , J Silvio Gutkind , Edward C Stites , et al., for their study on   Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation Chiara D Mancinelli , Joshua Levitz , David Eliezer , et al. for their research on Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains Dr. GPCR University Exciting news! We are pleased to announce the scheduled dates for our highly anticipated courses led by Dr. Terry Kenakin . As of July 31st, early-bird registration for our premium Ecosystem members will begin, allowing you to benefit from this exclusive discount. Be sure to mark your calendars and secure your spot for this extraordinary learning opportunity! Course Schedule and Details Every Thursday at 10 am EST Principles of Pharmacology in Drug Discovery I -   Techniques for Effective Lead Optimization of Candidate Molecules Dates:  September 5th to 26th, 2024 Registrants will learn: Essentials of measuring pharmacologic activity of ligands (affinity, efficacy, co-operativity). Application of this knowledge to determine the mechanism of action of new GPCR ligands. The required elements of a comprehensive and effective GPCR Discovery. 2. Principles of Pharmacology in Drug Discovery II -   Advanced Methods for the Optimization of Candidate Selection Dates:  October 3rd to 31st, 2024 Registrants will learn: The powerful applications of new cellular assays to determine GPCR ligand behavior in different functional systems. Understanding real-time kinetics to predict activity and in vivo target coverage. New ligands and new GPCR behaviors that produce unique drug profiles (i.e., intracellular ligands and signaling, location bias, signaling bias). GPCR Event Highlight Get ready for the  11th Adhesion GPCR Workshop! Hosted by the Adhesion GPCR Consortium, this exciting event will occur in lively and culturally rich Mexico City from October 23 to 25, 2024 . It is an opportunity to connect with like-minded scientists and researchers and gain valuable insights into the latest developments in adhesion GPCR biology. Take advantage of the chance to showcase your creativity by participating in the Logo Contest . Submit your design by August 15, 2024, and stand a chance to have your creation represent this prestigious event. Are you interested in becoming a sponsor? Take advantage of the sponsorship opportunities and elevate your brand's presence at this crucial scientific gathering. Feel free to reach out to us at Hello@DrGPCR.com .  Let’s dive into the   Classified GPCR News  from July 15th to 21st, 2024 GPCR Activation and Signaling Conformational dynamics underlying atypical chemokine receptor 3 activation RhoA-mediated G12-G13 signaling maintains muscle stem cell quiescence and prevents stem cell loss Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists GPCR Binders, Drugs, and more In silico exploration of 4(α-l-rhamnosyloxy)-benzyl isothiocyanate: A promising phytochemical-based drug discovery approach for combating multi-drug resistant Staphylococcus aureus Isolation, Structure Elucidation, and Biological Activity of the Selective TACR2 Antagonist Tumonolide and its Aldehyde from a Marine Cyanobacterium Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1 GPCRs in Cardiology, Endocrinology, and Taste GPCR-mediated regulation of beige adipocyte formation: Implications for obesity and metabolic health GPCRs in Neuroscience Chronic modulation of cAMP signaling elicits synaptic scaling irrespective of activity Neuronal GPCR NMUR-1 regulates energy homeostasis in response to pathogen infection GPCRs in Oncology and Immunology Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation Methods & Updates in GPCR Research A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models Reviews, GPCRs, and more Lessons from the physiological role of guanosine in neurodegeneration and cancer: Toward a multimodal mechanism of action? Structural and Molecular Insights into GPCR Function Entropy drives the ligand recognition in G-protein-coupled receptor subtypes Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3 Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains Industry News Novartis continues to deliver strong sales growth and core margin expansion in Q2; raises FY 2024 bottom-line guidance  Crinetics Pharmaceuticals to Report Second Quarter 2024 Financial Results on August 8, 2024 Dynamic nature of G-protein coupled receptors Septerna Secures $150 Million in Series B Financing to Advance Pipeline of Novel GPCR-targeted Medicines GPCR Events, Meetings, and Webinars NEW November 5 - 7, 2024 | 16th Annual PEGS Europe   September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs NEW   Senior or Lead Researcher   NEW Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Senior Scientist - Discovery Biotherapeutics Post-Doctoral Fellow/Trainee Scientist; Biochemistry, Cellular and Mechanistic Pharmacology; Lead Discovery and Optimization   Join the Dr. GPCR Ecosystem

📰 GPCR Weekly News, July 8 to 14, 2024 Hello readers! Check out our GPCR coverage for this week. We have 15 GPCR papers, three industry news, and two job ads.   This week's highlight includes congrats to: Remi Janicot , and Dr. Mikel Garcia-Marcos for their work on Get ready to sharpen your tools:A short guide to heterotrimeric G protein activity biosensors Marta Lopez-Balastegui , Antonella Di Pizio , Jiafei Mao , Jana Selent , et al. for their research on the Relevance of GPCR dynamics for receptor activation, signalling bias and allosteric modulation Drs. Badr Sokrat , Michel Bouvier , et al. for their study on the Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes Dr. GPCR University We are excited to announce the dates for our upcoming courses led by Dr. Terry Kenakin . Early-bird registration for premium Ecosystem members opens on July 31st , so mark your calendars and take advantage of the discount! Course Schedule and Details Every Thursday at 10 am EST Principles of Pharmacology in Drug Discovery I -   Techniques for Effective Lead Optimization of Candidate Molecules Dates:  September 5th to 26th, 2024 Overview: This course delves into the essential pharmacologic techniques and knowledge necessary to create a GPCR Target Program aimed at discovering new drugs. GPCRs remain one of the most prolific and fertile therapeutic drug targets. Principles of Pharmacology in Drug Discovery II -   Advanced Methods for the Optimization of Candidate Selection Dates:  October 3rd to 31st, 2024 Overview: Building on the basics covered in Course I, this course explores advanced methods in GPCR utilization for drug therapy. Topics include the complex pleiotropic behaviors of GPCRs and how these can be harnessed for innovative drug discovery. GPCR Event Highlight 11th Adhesion GPCR Workshop Hosted by the Adhesion GPCR Consortium, this event will be held in vibrant Mexico City from October 23 to 25, 2024. Join fellow scientists and researchers in person to stay updated with adhesion GPCR biology. Important Deadlines: Abstract Submission : July 22, 2024. Submit your abstract today; the deadline is fast approaching! Logo Contest : Unleash your creativity and submit your design by August 15, 2024. Sponsorship Opportunities : Explore options for sponsoring this prestigious event. For more information, contact us at Hello@DrGPCR.com . Let’s dive into the   Classified GPCR News  from July 8th to 14th, 2024 GPCR Activation and Signaling GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and independent desensitization mechanisms Get ready to sharpen your tools:A short guide to heterotrimeric G protein activity biosensors Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach Mechanisms controlling haemolymph circulation under resting conditions in the chagas disease vector Rhodnius Prolixus (Stål ) Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes GPCRs in Neuroscience An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake The tick Ixodes scapularis has five different GPCRs specifically activated by ACP (adipokinetic hormone/corazonin-related peptide) GPCRs in Oncology and Immunology S1P Signaling Genes as Prominent Drivers of BCR-ABL1-Independent Imatinib Resistance and Six Herbal Compounds as Potential Drugs for Chronic Myeloid Leukemia Methods & Updates in GPCR Research High-throughput G protein-coupled receptor-based autocrine screening for secondary metabolite production in yeast Reviews, GPCRs, and more Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation Structural and Molecular Insights into GPCR Function Structural Mass Spectrometry Captures Residue-Resolved Comprehensive Conformational Rearrangements of a G Protein-Coupled Receptor Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models Probing the energy landscape of the lipid interactions of the serotonin1A receptor Industry News Neurocrine Biosciences Announces Conference Call and Webcast of Second Quarter 2024 Financial Results G-Protein Coupled Receptors Global Market 2024 To Reach $4.09 Billion By 2028 At Rate Of 6.5% Trevena Announces $2M Non-Dilutive Financing Tranche and Reduction in Outstanding Liabilities in Connection with Existing ex-US Royalty Financing EuroscreenFast and GW Vitek Announce Strategic Distribution Partnership in Korea   GPCR Events, Meetings, and Webinars September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW   Postdoctoral Research Associate   Senior Scientist - Discovery Biotherapeutics Post-Doctoral Fellow/Trainee Scientist; Biochemistry, Cellular and Mechanistic Pharmacology; Lead Discovery and Optimization   Director/Sr. Director GPCR Drug Discovery Biologist   Post-Doctoral Scientist- Molecular Pharmacology (FDE) Join Dr. GPCR Ecosystem

Hello everyone!  Check out our latest collection of 25 cutting-edge research papers on GPCRs and exciting updates on industry news related to GPCRs!   This week's highlight includes congrats to Edda Matthees , Drs.  Evi Kostenis , Carsten Hoffmann , et al., for their work on GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism Dr. Gunnar Schulte  for his study on the International Union of Basic and Clinical Pharmacology. CXV: The Class F of G Protein-Coupled Receptors Yusman Manchanda , Dr. Alejandra Tomas , et al. for their research on Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling Mónica Navarro-Sánchez , Drs. Ross Bathgate , Francisco Olucha-Bordonau , et al.    for their investigation on Modulation of contextual fear acquisition and extinction by acute and chronic relaxin-3 receptor (RXFP3) activation in the rat retrosplenial cortex Sarah Bernhard , Drs. Jianming Han , Tao Che  for their analysis of GPCR-G protein selectivity revealed by structural pharmacology Yao Lu , Drs Christopher Langmead ,  Gregory Stewart , et al. for their study on Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia Dr. GPCR University The wait is finally over! We're thrilled to announce the dates for our upcoming courses led by the renowned Dr. Terry Kenakin . Mark your calendars because registration opens on July 18, 2024! These engaging online courses will take place every Thursday at 10 am EST. Here’s a sneak peek at what you can expect: Principles of Pharmacology in Drug Discovery I - Techniques for Effective Lead Optimization of Candidate Molecules Dates:  September 5th to 26th, 2024 Overview: GPCRs have been and arguably still are the most prolific and fertile therapeutic drug targets; this course describes the essential pharmacologic techniques and knowledge required to create a GPCR Target Program to discover new Drugs. Principles of Pharmacology in Drug Discovery II - Advanced Methods for the Optimization of Candidate Selection Dates:  October 3rd to 31st, 2024 Overview: This course continues with the basics learned in Course 1 and extends the ideas to apply GPCR utilization in drug therapy . Specifically, the ideas discussed cover the complex pleiotropic behaviors of GPCRs and how these may be exploited for new drug discovery. GPCR Event Highlight Immerse yourself in the cutting-edge world of adhesion GPCR research at the highly anticipated 11th Adhesion GPCR Workshop , hosted by the Adhesion GPCR Consortium. Taking place in the vibrant setting of Mexico City, this face-to-face gathering scheduled for October 23 to 25, 2024 , is poised to be a crucial meeting for scientists and researchers dedicated to the study of adhesion GPCR biology. Important Deadlines: Abstract Submission :  July 22, 2024. Submit your abstract today; you have less than two weeks! Logo Contest :   Unleash your creativity and submit your design by August 15th, 2024 Sponsorship Opportunities :  Explore sponsorship options for this prestigious event. For more information, contact us at Hello@DrGPCR.com .   Let’s dive into the   Classified GPCR News  from July 1 to 7, 2024 GPCR Activation and Signaling GPCR-MAPK signaling pathways underpin fitness trade-offs in whitefly G protein-coupled receptor kinases in hypertension: physiology, pathogenesis, and therapeutic targets GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism The roles of RGS proteins in cardiometabolic disease GPCR Binders, Drugs, and more Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders GPCRs in Cardiology, Endocrinology, and Taste Geosmin, a Food- and Water-Deteriorating Sesquiterpenoid and Ambivalent Semiochemical, Activates Evolutionary Conserved Receptor OR11A1 Tongue-on-a-Chip: Parallel Recording of Sweet and Bitter Receptor Responses to Sequential Injections of Pure and Mixed Sweeteners GPCRs involved in metabolic diseases: pharmacotherapeutic development updates Targeting G protein-coupled receptors for heart failure treatment RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB1, CB2, GPR18 and GPR55 cannabinoid receptors GPCRs in Neuroscience Neuron specific quantitation of Gαolf expression and signaling in murine brain tissue Modulation of contextual fear acquisition and extinction by acute and chronic relaxin-3 receptor (RXFP3) activation in the rat retrosplenial cortex Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia Single nucleotide variations encoding missense mutations in G protein-coupled receptors may contribute to autism GPCRs in Oncology and Immunology Emerging GPCR targets for AUD: Insights from preclinical studies CB2 stimulation of adipose resident ILC2s orchestrates immune balance and ameliorates type 2 diabetes mellitus Methods & Updates in GPCR Research Computational modelling of dynamic cAMP responses to GPCR agonists for exploration of GLP-1R ligand effects in pancreatic β-cells and neurons The application of artificial intelligence to accelerate G protein-coupled receptor drug discovery The application of targeted protein degradation technologies to G protein-coupled receptors Unravelling G protein-coupled receptor signalling networks using global phosphoproteomics Reviews, GPCRs, and more International Union of Basic and Clinical Pharmacology. CXV: The Class F of G Protein-Coupled Receptors Structural and Molecular Insights into GPCR Function Cryo-EM advances in GPCR structure determination GPCR-G protein selectivity revealed by structural pharmacology Industry News Neurocrine Biosciences Announces U.S. FDA Accepts New Drug Applications and Grants Priority Review for Crinecerfont for Pediatric and Adult Patients with CAH   adMare BioInnovations Expands with New Wet Laboratory Space in Vancouver   ThirtyFiveBio receives grant to continue work on GPR35 blockers   GPCR Events, Meetings, and Webinars September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT   Principal Scientist, In vitro pharmacology   NEW Senior Scientist - Discovery Biotherapeutics NEW Post-Doctoral Fellow/Trainee Scientist; Biochemistry, Cellular and Mechanistic Pharmacology; Lead Discovery and Optimization   Director/Sr. Director GPCR Drug Discovery Biologist   Post-Doctoral Scientist- Molecular Pharmacology (FDE) Research Assistant     Join Dr. GPCR Ecosystem

Hello everyone! We have gathered 24 new research papers on GPCRs and updates on industry news related to GPCRs.   This week's highlight includes congrats to: Drs. Bryan Roth and Brian Krumm   for their study on Molecular glues as potential GPCR therapeutics Drs. András Tóth , László Hunyady , et al. for their work on G protein-coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling Drs.   Kawthar Belkacemi , Philippe Rondard , Jean-Philippe Pin , and Laurent Prézeau ,   for their research on Heterodimers revolutionize the field of metabotropic glutamate receptors Kara Anazia , Dr. Matthew Eddy , et al. for their investigation on Interaction Networks within Disease-Associated GαS Variants Characterized by an Integrative Biophysical Approach   Dr. GPCR University We're thrilled to announce that Dr. Terry Kenakin  will lead two brand-new, back-to-back courses tailored for the Dr. GPCR Ecosystem this fall. Mark your calendars for September and October 2024, and stay tuned for registration details coming this month. These online courses will be held on Thursdays at 10 am EST. Save the dates: Course 1: Strategies for Successful Lead Optimization of Candidate Molecules Dates:  September 5th to 26th, 2024 Course 2: Advanced Methods for the Optimization of Candidate Selection Dates:  October 3rd to 31st, 2024 GPCR Event Highlight Join us for an in-person event with the Adhesion GPCR Consortium: the 11th Adhesion GPCR Workshop, which will be held in vibrant Mexico City from October 23 to 25, 2024. This key event will delve into adhesion GPCR Biology. Important Deadlines: Abstract Submission :  July 22, 2024. Submit your abstract today! Logo Contest :   Unleash your creativity and submit your design by August 15th, 2024 Sponsorship Opportunities :  Explore sponsorship options for this prestigious event. For more information, contact us at Hello@DrGPCR.com .   Let’s dive into the   Classified GPCR News  from June 24th to 30th, 2024 Adhesion GPCRs Novel Isoforms of Adhesion G Protein-Coupled Receptor B1 (ADGRB1/BAI1) Generated from an Alternative Promoter in Intron 17 The adhesion-GPCR ADGRF5 fuels breast cancer progression by suppressing the MMP8-mediated antitumorigenic effects GPR56: A potential therapeutic target for neurological and psychiatric disorders GPCR Activation and Signaling Molecular basis for the activation of PAF receptor by PAF Heterodimers revolutionize the field of metabotropic glutamate receptors Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics Structural insights into ligand recognition and activation of the succinate receptor SUCNR1 G protein-coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling Interaction Networks within Disease-Associated GαS Variants Characterized by an Integrative Biophysical Approach Redox-modulated SNX25 as a novel regulator of GPCR-G protein signaling from endosomes Cellular lipids regulate the conformational ensembles of the disordered intracellular loop 3 in β2-adrenergic receptor Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR GPCR Binders, Drugs, and more Molecular glues as potential GPCR therapeutics A high-affinity, cis-on photoswitchable beta blocker to optically control β2-adrenergic receptors in vitro and in vivo GPCRs in Neuroscience Elucidating the activation mechanism of the proton-sensing GPR68 receptor Astrocytic GPCR signaling in the anterior cingulate cortex modulates decision making in rats Translation-independent association of mRNAs encoding protomers of the 5-HT 2A -mGlu2 receptor complex in living cells GPCRs in Oncology and Immunology Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy Agonists of galanin subtype 2 receptor may prevent pancreatic cancer and agonists of angiotensin II type 2 receptor may prevent colorectal cancer Distinct Activation Mechanisms of CXCR4 and ACKR3 Revealed by Single-Molecule Analysis of their Conformational Landscapes Methods & Updates in GPCR Research Protocol to visualize and quantify the COPII concentration and anterograde transport of nascent G protein-coupled receptors Effects of an external static EF on the conformational transition of 5-HT1A receptor: A molecular dynamics simulation study Monitoring norepinephrine release in vivo using next-generation GRABNE sensors Structural and Molecular Insights into GPCR Function Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor Industry News Nxera Pharma Receives US$10 Million from AbbVie as Collaboration Targeting Neurological Diseases Achieves First R&D Milestone Tectonic bets on GPCR heart failure drug following reverse merger with Avrobio Lilly signs $140M upfront partnership with Radionetics in latest radiopharma play   GPCR Events, Meetings, and Webinars September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Scientist; Biochemistry, Cellular and Mechanistic Pharmacology; Lead Discovery and Optimization   NEW Director/Sr. Director GPCR Drug Discovery Biologist   HIGHLIGHT   Principal Scientist, In vitro pharmacology   Post-Doctoral Scientist- Molecular Pharmacology (FDE) Research Assistant   Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Join Dr. GPCR Ecosystem

Greetings to all! This Thursday, explore the latest content on GPCRs, which includes 29 informative research papers and industry news. Stay informed about the most recent developments in GPCR research and industry updates. This week's highlight includes congrats to: Ya-Tzu Li for her contributor article titled Do You Believe AI Could Accelerate Drug Discovery? Shane Wright, Michel Bouvier, et al., for their work on Conformation- and activation-based BRET sensors differentially report on GPCR-G protein coupling Samuel Liu, Preston Anderson, Sudarshan Rajagopal, Robert Lefkowitz, Howard Rockman for their review G Protein-Coupled Receptors: A Century of Research and Discovery Dr. GPCR University We are excited to announce that Dr. Terry Kenakin will conduct two back-to-back courses this fall. Save the September and October 2024 dates, and look for registration details in July. The two back-to-back courses are new and specially tailored to the Dr. GPCR Ecosystem and our community. The classes will be online Thursdays from 10 am EST. Save the dates from September 5th to 26th, 2024, to learn about Strategies for Successful Lead Optimization of Candidate Molecules. Save the dates from October 3rd to 31st, 2024, to learn more about the Advanced Methods for the Optimization of Candidate Selection. GPCR Event Highlight Join us for a special in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop. This exciting event will occur in lively Mexico City from October 23 to 25, 2024, and will be a cornerstone for discussions in adhesion GPCR Biology. NEW DEADLINE July 22, 2024: Submit your abstract today! Logo Contest: Unleash your creativity by designing the event logo! Submit your entries by August 15th, 2024. Sponsorship Opportunities: Explore sponsorship possibilities for this prestigious event. For more details, contact us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from June 17th to 23rd, 2024. GPCR Activation and Signaling GPCR-dependent and -independent arrestin signaling Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling Exploring the Activation Mechanism of the GPR183 Receptor GPCR Binders, Drugs, and more Target-based discovery of antagonists of the tick (Rhipicephalus microplus) kinin receptor identifies small molecules that inhibit midgut contractions Ligand-based analysis of the antifungal potential of phytosterols and triterpenes isolated from Cryptostegia grandiflora against Candida auris FKBP12 Development and therapeutic perspectives of CXCR4 antagonists for disease therapy GPCRs in Cardiology, Endocrinology, and Taste Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions GPCRs in Neuroscience Male-specific behavioral and transcriptomic changes in aging C. elegans neurons Activation of Gs Signaling in Cortical Astrocytes Does Not Influence Formation of a Persistent Contextual Memory Engram β-arrestins are scaffolding proteins required for Shh-mediated axon guidance GPCRs in Oncology and Immunology Regulator of G protein signaling 16 restrains apoptosis in colorectal cancer through disrupting TRAF6-TAB2-TAK1-JNK/p38 MAPK signaling Metallo-protease Peptidase M84 from Bacillusaltitudinis induces ROS-dependent apoptosis in ovarian cancer cells by targeting PAR-1 G protein-coupled receptors related to autoimmunity in postural orthostatic tachycardia syndrome The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer Identification of a G-protein coupled receptor-related gene signature through bioinformatics analysis to construct a risk model for ovarian cancer prognosis GprC of the nematode-trapping fungus Arthrobotrys flagrans activates mitochondria and reprograms fungal cells for nematode hunting Role and recent progress of P2Y12 receptor in cancer development Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia Methods & Updates in GPCR Research The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER Optical Control of TRPV1 Channels In Vitro with Tethered Photopharmacology Deuteration as a General Strategy to Enhance Azobenzene-Based Photopharmacology Optical Control of Cell-Surface and Endomembrane-Exclusive β-Adrenergic Receptor Signaling Conformation- and activation-based BRET sensors differentially report on GPCR-G protein coupling Reviews, GPCRs, and more Proteome-wide analysis reveals G protein-coupled receptor-like proteins in rice (Oryza sativa) G Protein-Coupled Receptors: A Century of Research and Discovery Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision Structural and Molecular Insights into GPCR Function Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103 Industry News EY Announces Scott Struthers, Ph.D., CEO and Founder of Crinetics Pharmaceuticals, as an Entrepreneur Of The Year® 2024 Pacific Southwest Award Winner Monlunabant by Inversago Pharma for Metabolic Syndrome: Likelihood of Approval Tectonic bets on GPCR heart failure drug following reverse merger with Avrobio Addex Pharma unveils new mGlu7 receptor negative allosteric modulators Trevena Announces Preclinical TRV045 Data Providing Insight Into Novel Mechanism of Analgesic Effect in Chronic Neuropathic Pain Model and Demonstrating Statistically Significant Anti-Seizure Activity in Epilepsy Models Biophysicists decipher functionality of adrenaline-binding receptor Tectonic plates more than $130m in new funding and goes public GPCR Events, Meetings, and Webinars NEW June 27, 2024 | FREE GPCR Forum ECI Zoominar June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 NEW September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology NEW Post-Doctoral Scientist- Molecular Pharmacology (FDE) NEW Research Assistant Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Join Dr. GPCR Ecosystem

The advent of AlphaFold2 (AF2) has brought AI applications in drug development to unprecedented heights. Its groundbreaking ability to accurately predict protein structures is transformative for identifying new drug targets and designing effective drug molecules. G protein-coupled receptors (GPCRs) are major drug targets, yet their complex and dynamic structures pose significant challenges to traditional structural analysis methods. By using machine learning, AF2 can accurately predict the 3D structures of GPCRs with atomic-level accuracy and remarkable scalability, providing crucial structural insights for drug development. The AlphaFold database encompasses over 200 million proteins, aiding structural biology, protein design, and function prediction. However, the impact on structure-based ligand discovery remained uncertain due to the necessity for accurately modeled binding sites. This study examines these concerns by comparing AF2's predictions with experimental structures for docking experiments. Lyu et al. prospectively docked ultra-large libraries of molecules against unrefined AF2 models of the σ2 and 5-HT2A serotonin receptors, comparing the results to docking against experimental structures. They found that AF2 models achieved accurate side-chain predictions and successfully docked high-affinity ligands. For the σ2 receptor, AF2 predicted side-chain conformations with an RMSD of 1.1 Å from the crystal structure. Docking 490 million molecules against the σ2 receptor's AF2 model yielded a 54% hit rate, comparable to the 51% hit rate using the crystal structure. For the 5-HT2A receptor, AF2 models showed some variations at key residues, and docking 1.6 billion molecules resulted in high hit rates. Of 161 molecules tested, 42 substituted more than 50% of [³H]-LSD at 10 μM, achieving a 26% hit rate. The highest affinity compounds (15 to 24 nM) were identified from AF2 docking. Functional activity of selected compounds was assessed across 5-HT2A, 5-HT2B, and 5-HT2C receptors, with several compounds demonstrating subtype selectivity and high potency, some with sub-nanomolar EC50 values, indicating strong and selective receptor binding. This validates AF2's potential in enhancing drug discovery precision and efficiency. Despite its transformative potential, AI in drug development faces several challenges. One significant concern is the reliance on data quality and quantity, where inaccuracies or biases in training data can lead to flawed predictions. Moreover, advanced AI models like AlphaFold3, which can predict complex protein-molecule interactions and post-translational modifications, are now accessible only via a restricted server, unlike its predecessor AlphaFold2. This proprietary nature limits direct access to the model and imposes a cap on daily predictions. The lack of transparency surrounding its operations and usage constraints restricts extensive academic scrutiny. Addressing these challenges is crucial to fully harness AI's potential in accelerating drug discovery and optimizing therapeutic outcomes. Looking ahead, AI offers significant advantages in drug development, such as the ability to tackle complex targets and accurately predict protein-molecule interactions. To fully harness these benefits, it is essential to keep updating and refining the databases with high-quality data. This effort will help resolve issues related to data accuracy and bias, leading to more dependable predictions. Additionally, transparency in AI models and their operations is crucial for building trust and allowing for academic review. Furthermore, AI's role in structural biology and drug design is set to spark innovation in automated screening and large-scale data analysis, paving the way for a new era in precision medicine and medical research. References: Lyu, J. et al. AlphaFold2 structures guide prospective ligand discovery. Science https://doi.org/10.1126/science.adn6354 (2024) Abramson, J., Adler, J., Dunger, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024). https://doi.org/10.1038/s41586-024-07487-w

Hi everyone, Take a moment to explore our latest coverage of GPCRs this week, which includes 7 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Dr. John Teye Azietaku for his contributor article on Unveiling GPCR Priming: The Hidden Synergy in Cellular Signalling Alberto Gonzalez-Hernandez, Hermany Munguba, Joshua Levitz for their work on Emerging modes of regulation of neuromodulatory G protein-coupled receptors Dr. GPCR University We are thrilled to announce that Dr. Terry Kenakin will conduct two consecutive courses in September and October 2024. Stay tuned for more details, and mark your calendars for registration opening in July 2024. Dr. GPCR Podcast Tune into the 156th episode of the Dr. GPCR Podcast, featuring Dr. Justin English on "Empowering Drug Discovery for the GPCR Community"! Experience the full impact of our discussions with our new video format. Witness the passion and excitement of our guests as you catch up on missed episodes. GPCR Event Highlight We’re excited to announce our in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop. Join us in vibrant Mexico City from October 23 to 25, 2024, for this key event in adhesion GPCR Biology. Present Your Research: Submit your abstract by June 24th for priority consideration or by July 22nd for the second round. Logo Contest: Showcase your creativity by designing the event logo! Submit your entries by August 15th, 2024. Sponsorship Opportunities: We’re offering sponsorship opportunities for this prestigious event. For more details, contact us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from June 10th to 16th, 2024. GPCR Activation and Signaling Emerging modes of regulation of neuromodulatory G protein-coupled receptors GPCRs in Cardiology, Endocrinology, and Taste Chamber-specific contractile responses of atrial and ventricular hiPSC-cardiomyocytes to GPCR and ion channel targeting compounds: A microphysiological system for cardiac drug development GPCRs in Neuroscience Astrocytic PAR1 and mGluR2/3 control synaptic glutamate time course at hippocampal CA1 synapses Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse Alcohol consumption does not impact delta and kappa opioid receptor-mediated synaptic depression in dorsolateral striatum of adult male mice Methods & Updates in GPCR Research RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges Structural and Molecular Insights into GPCR Function Structural perspectives on chemokine receptors Industry News Exscientia Appoints New Leaders to Strengthen the Impact of Integrated Technologies and Focus Clinical Development Expertise in Oncology Octant Bio will be at the Goldman Sachs Global Healthcare Conference Crinetics Pharmaceuticals gets grant for patent granted for oral method to suppress hormones GPCR Events, Meetings, and Webinars June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

G protein-coupled receptors (GPCRs) are a vast family of membrane-bound proteins crucial for transmitting external stimuli into intracellular signals, thereby influencing numerous physiological processes. These receptors typically engage specific G protein subtypes, such as Gs, Gi/o, Gq/11, and G12/13, at the initial GPCR-G protein association step, ensuring precise downstream signalling activation. Traditionally, it was believed that GPCRs selectively activate only their cognate G protein subtypes, avoiding interactions with non-cognate G proteins [1]. However, recent studies have unveiled a complex layer of GPCR functioning, introducing the concept of 'unproductive coupling'[1] and a fascinating phenomenon known as GPCR priming [2]. The concept of unproductive coupling was highlighted by Okashah et al. in 2020 [1]. Using BRET based approaches, the Gs-coupled vasopressin V2 receptor (V2R) was shown to form a stable complex with the non-cognate G12 protein in response to arginine vasopressin. Surprisingly, this interaction did not result in G12 activation, even in the presence of GTP, which is typically necessary for G protein activation. Instead, G12 overexpression inhibited V2R downstream signalling, including β-arrestin recruitment and receptor internalization. This unproductive coupling revealed that non-cognate G protein interactions could modulate GPCR signalling pathways without initiating traditional activation sequences. In 2017, Gupte et al. introduced GPCR priming, which posits that non-cognate G proteins can enhance the coupling efficiency of cognate G proteins to GPCRs, thereby amplifying canonical downstream signalling [2]. This priming effect occurs through non-functional interactions between non-cognate G proteins and GPCRs, facilitating subsequent coupling of cognate G proteins and promoting enhanced signalling. Gupte et al. utilized a systematic protein affinity strength modulation (SPASM) technique to show that Gq proteins could bolster Gs dependent-β2-adrenergic receptor-mediated cAMP signalling, while Gs proteins similarly enhanced Gq dependent-vasopressin receptor-mediated IP1 accumulation. The enhanced signalling observed in GPCR priming is attributed to the formation of temporal non-cognate-GPCR conformational states, which enable more efficient interactions between the GPCR and the cognate Gα C terminus [2, 3]. This suggests that the non-cognate G proteins, although not activating downstream pathways directly, prepare the GPCR in a manner that optimizes subsequent cognate G protein activation. Using CRISPR-Cas9 knockout HEK cells lacking Gs proteins, a study by Stallaert et al. in 2017 showed that Gs played a pivotal role in calcium signalling at the β2-adrenergic receptors (β2AR) [4]. Overall, the increased calcium signalling was attributed to the release of ATP via β2AR-Gs mediated activation, which subsequently transactivates purinergic receptors through Gq in intracellular stores [4]. Thus, this finding raises the possibility that GPCR priming might result not only from intricate receptor-G protein interactions but also from the influence of downstream effector mechanisms. However, IP1 signalling through the non-cognate Gq was not important for the increased β2AR-Gs-mediated cAMP levels in response to isoproterenol. [2]. GPCR priming opens new avenues for understanding the nuanced regulatory mechanisms governing GPCR signalling. It challenges the traditional view of strict cognate G protein coupling and suggests a more dynamic interaction landscape where non-cognate G proteins play a critical preparatory role. This has significant implications for drug development, as targeting these non-cognate interactions could lead to novel therapeutic strategies for modulating GPCR activity. In conclusion, GPCR priming represents a compelling area of research that promises to deepen our understanding of cellular signalling networks. Continued exploration into the molecular mechanisms underlying this phenomenon could unveil new dimensions of GPCR functionality and offer innovative approaches to treating a wide range of diseases. References 1.      Okashah, N., et al., Agonist-induced formation of unproductive receptor-G(12) complexes. Proc Natl Acad Sci U S A, 2020. 117(35): p. 21723-21730. 2.      Gupte, T.M., et al., Priming GPCR signaling through the synergistic effect of two G proteins. Proceedings of the National Academy of Sciences, 2017. 114(14): p. 3756-3761. 3.      Hilger, D., et al., Structural insights into differences in G protein activation by family A and family B GPCRs. Science, 2020. 369(6503). 4.      Stallaert, W., et al., Purinergic Receptor Transactivation by the β(2)-Adrenergic Receptor Increases Intracellular Ca(2+) in Nonexcitable Cells. Mol Pharmacol, 2017. 91(5): p. 533-544.

Hi everyone, Please take a moment to explore our most recent coverage of GPCRs this week, which includes 15 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Dr. Monserrat Avila-Zozaya for her contributor article on Navigating the Signaling Network: RTK and GPCR Crosstalk Uncovered Drs. Jürgen Wess and Liu Liu for their study on A novel function of the M2 muscarinic receptor Drs. Zhan-Guo Gao, Mansour Haddad, and Kenneth A Jacobson for their work on A2B adenosine receptor signaling and regulation Dr. GPCR University We are excited to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. More details will be shared soon, and registration will open in July 2024. Dr. GPCR Podcast The 155th episode of the Dr. GPCR Podcast features a recap of the Endocrine Metabolic GPCRs 2024 with the organizers, Drs. Aylin Hanyaloglu, Caroline Gorvin, and Alejandra Tomas. It is now available for viewing in video format on our website. Catch up on missed episodes and immerse yourself in the visual experience! GPCR Event Highlight We are thrilled to share the news of our in-person event in partnership with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop. This significant event in adhesion GPCR Biology will be held in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community to present your research—submit your abstract using this form. Deadline 1st round priority: June 24th / 2nd round: July 22th Do you have an artistic side? If so, participate in our logo contest for the event! Submit your logo and review the rules. The contest deadline is August 15th, 2024. We are also offering sponsorship opportunities for this exciting event, which brings together scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from June 3rd to June 9th, 2024. Adhesion GPCRs A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer GPCR Activation and Signaling The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity Differential activation of rhodopsin triggers distinct endocytic trafficking and recycling in vivo via differential phosphorylation Increased transcriptional elongation and RNA stability of GPCR ligand binding genes unveiled via RNA polymerase II degradation Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors Kinetic Model for the Desensitization of G Protein-Coupled Receptor RNA-seq screening and gene function analysis uncover GPR183 as a key mediator for methionine to stimulate milk synthesis in mouse mammary epithelial cells GPCR Binders, Drugs, and more Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1 GPCR function in autophagy control: a systematic approach of chemical intervention Methods & Updates in GPCR Research ORP9-PH domain-based fluorescent reporters for visualizing phosphatidylinositol 4-phosphate dynamics in living cells Reviews, GPCRs, and more Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic-pituitary-gonadal axis1 A novel function of the M2 muscarinic receptor A2B adenosine receptor signaling and regulation Novel medications for problematic alcohol use Structural and Molecular Insights into GPCR Function Structural basis for recognition of 26RFa by the pyroglutamylated RFamide peptide receptor Industry News NanoImaging Services and Cube Biotech Collaborate to Enhance Cryo-EM Enabled Gene to Structure Workflow Domain Therapeutics Strengthens Its Intellectual Property for Its Series of Treg Depleting anti-CCR8 Antibodies, Including Best-in-class Candidate DT-7012 Crinetics Announces Positive Initial Findings at ENDO 2024 for Atumelnant in Two Ongoing, Open-Label Studies for the Treatment of Congenital Adrenal Hyperplasia (CAH) and ACTH-Dependent Cushing’s Syndrome (ADCS) Septerna Presents Preclinical Data at ENDO 2024 Highlighting Therapeutic Potential of its GPCR Drug Discovery Platform GPCRs and Emotional Pain: Exploring Non-Narcotic Pathways to Relief GPCR Events, Meetings, and Webinars June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

One fascinating aspect of the cellular signaling network is the crosstalk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). GPCRs, known for their involvement in a myriad of physiological processes, mediate mostly signaling through heterotrimeric G proteins. On the other hand, RTKs play pivotal roles in growth factor signaling, regulating cell growth, differentiation, and survival. The interaction between these two receptor types raises intriguing questions about how their signaling pathways intersect and influence each other to orchestrate cellular responses. The cross-talk between growth factor receptors and GPCRs is an intriguing area of study. Recently, Suchismita Roy et al. have explored how growth factors can modulate canonical G protein signaling, shedding light on molecular mechanisms with significant implications for both physiology and pathology. The primary research question addressed in this study was: How do growth factors, specifically through RTKs, modulate canonical heterotrimeric G protein signaling? The researchers focused on the phosphorylation of the G protein subunit Gαi at specific residues within three strategic hotspots: the P loop, the interdomain cleft, and the C terminus. They employed a series of phospho-mimicking mutants and assays such as linear ion trap mass spectrometry, BRET, pull down, and transwell cell migration assays to investigate the effects of these modifications on key signaling events such as receptor recruitment, trimer dissociation, cAMP inhibition, and chemotaxis. The study revealed that the epidermal growth factor-induced phosphorylation of Gαi at specific residues predominantly inhibits ligand-induced signaling while promoting constitutive Gβγ signaling. Key findings include: Phosphorylation Hotspots: P Loop (Ser44, Ser47, Thr48): Impairs ligand-stimulated Gβγ release and cAMP suppression, potentially acting as dominant-negative proteins. Interdomain Cleft (Ser151, Tyr154, Tyr155): Phosphorylation at Tyr154 and Tyr155 impaired ligand-stimulated Gβγ release, cAMP suppression, and chemotaxis while enhancing constitutive Gβγ signaling. Computational analyses indicated that these modifications favor the nucleotide-free state of Gαi. C Terminus (Tyr320): Phosphorylation at Tyr320 disrupted Gβγ binding, receptor coupling, and ligand-stimulated signaling, resulting in impaired chemotaxis. Notably, the Y320F mutation restored some signaling capabilities, emphasizing Tyr320's role in membrane localization and signaling efficiency. Mechanisms of Inhibition: The study identified three distinct mechanisms by which phosphorylation inhibits canonical signaling, based on the location of the phosphosites within the G protein. Signaling Pathway Segregation: Phosphorylation events in the interdomain cleft and P loop uncouple G proteins from GPCRs, leading to segregation of RTK-to-Gαi pathways from canonical GPCR-to-Gαi pathways. These findings have broad implications for understanding cellular signaling in both normal physiology and pathological conditions. The ability of growth factors to modulate G protein signaling through specific phosphorylation events highlights a nuanced regulatory mechanism that could be crucial in contexts such as cancer progression and wound healing. For instance, the sequestration of G proteins from canonical GPCR-dependent pathways by growth factor signaling might contribute to altered cellular behaviors in cancer, promoting uncontrolled cell migration and invasion. Moreover, the study's insights into the structural and functional consequences of specific phosphorylation events provide a deeper understanding of the molecular basis for cross-talk between RTKs and GPCRs. This knowledge could inform the development of therapeutic strategies aimed at targeting specific phosphorylation events to modulate G protein signaling in disease. In conclusion, this research elucidates the molecular mechanisms by which growth factors influence G protein signaling, revealing the strategic importance of phosphorylation at specific residues. These findings enhance our understanding of cellular signaling dynamics and open new avenues for therapeutic intervention in diseases characterized by dysregulated signaling pathways. Reference Roy, S., Sinha, S., Silas, A. J., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024). Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors. Science signaling, 17(839), eade8041. https://doi.org/10.1126/scisignal.ade8041

Hello everyone! Take a moment to browse our latest coverage of GPCRs this week, featuring 24 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Inês Pinheiro, for her Dr. GPCR contributor article Canonical chemokine receptors as scavenging “decoys” Shivani Sachdev, Brendan Creemer, Thomas Gardella, and Ross Cheloha for their work on Highly biased agonism for GPCR ligands via nanobody tethering Elk Kossatz, Michel Bouvier, Jana Selent, et al. for their study on G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits Dr. GPCR University We are excited to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. More details will be shared soon, and registration will open in July 2024. Dr. GPCR Podcast Episode 154 of the Dr. GPCR Podcast on Self-Learning, Collaboration, and Delegation in Science with Dr. Badr Sokrat is live! You can now watch podcast episodes in video format on our website. Catch up on missed episodes and enjoy the visual experience! GPCR Event Highlight We are excited to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop will take place in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community to share your research—submit your abstract using this form. We are also offering sponsorship opportunities for this exciting event, which unites scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 27th to June 2nd, 2024. GPCR Activation and Signaling Highly biased agonism for GPCR ligands via nanobody tethering Mechanistic insights into G-protein activation via phosphorylation mediated non-canonical pathway GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits GPCRs in Cardiology, Endocrinology, and Taste The full-length TSH receptor is stabilized by TSH ligand Cardiomyocyte-specific overexpression of GPR22 ameliorates cardiac injury in mice with acute myocardial infarction GPCRs in Neuroscience Voltage tunes mGlu5 receptor function, impacting synaptic transmission Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an in silico approach GRN knockdown regulates the expression and alternative splicing of genes associated with aphasia-related diseases in PC12 cells 17-β-estradiol potentiates the neurotrophic and neuroprotective effects mediated by the dopamine D3/acetylcholine nicotinic receptor heteromer in dopaminergic neurons A new GRAB sensor reveals differences in the dynamics and molecular regulation between neuropeptide and neurotransmitter release GPCRs in Oncology and Immunology Neurotoxicity and accumulation of CPPD quinone at environmentally relevant concentrations in Caenorhabditis elegans Comparison of infectious complications with BCMA-directed therapies in multiple myeloma Glucose and HODEs regulate Aspergillus ochraceus quorum sensing through the GprC-AcyA pathway Deciphering the genetic landscape of lumpy skin disease: Unraveling variable virulence through comprehensive genome sequence analysis in India Methods & Updates in GPCR Research Engineering G protein-coupled receptors for stabilization Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism Chemogenetic Signaling in Space and Time: Considerations for Designing Neuroscience Experiments Using DREADDs Reviews, GPCRs, and more ERNEST COST action overview on the (patho)physiology of GPCRs and orphan GPCRs in the nervous system Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy Single transmembrane GPCR modulating proteins: neither single nor simple Structural and Molecular Insights into GPCR Function Insights on the G protein-coupled receptor helix 8 solution structure and orientation using a neurotensin receptor 1 peptide Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies Industry News Structure Therapeutics Reports Positive Topline Data from its Phase 2a Obesity Study and Capsule to Tablet PK Study for its Oral Non-Peptide Small Molecule GLP-1 Receptor Agonist GSBR-1290 Crinetics Pharmaceuticals Appoints Robert M. Cuddihy, M.D., as Senior Vice President of Medical Affairs Septerna to Participate in the Jefferies Global Healthcare Conference Crinetics Announces Positive Initial Findings At Endo 2024 For Atumelnant In Two Ongoing, Open-Label Studies For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Acth-Dependent Cushing’s Syndrome (ADCS) Nxera Pharma to Receive $4.6 Million in Milestone Payments from Centessa Pharmaceuticals CB1 receptor inverse agonist improves lung functioning in preclinical asthma GPCR Events, Meetings, and Webinars June 2 - 7, 2024 | Chemotactic Cytokines June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology PostDoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

The immune system depends on chemokines to direct cell migration during immune surveillance and inflammation, as well as to play vital roles in the development, maturation, and homing of lymphocytes and the development of organs. However, an imbalance in the chemokine system can also contribute to various diseases, such as inflammatory conditions and cancer. In all these situations, chemokines interact with seven-transmembrane chemokine-type G protein-coupled receptors (chemokine receptors, CKRs) and glycosaminoglycans (GAGs) to regulate the movement of leukocytes throughout the body, ensuring a functional immune system and an effective response to inflammatory stimuli (Proudfoot, A. E, 2002). In humans there are approximately 45 chemokines, 19 chemotactic or G-protein coupled chemokine receptors (CKRs) that signal via Gαi and 4 official atypical chemokine receptors (ACKRs) which engage in ligand scavenging and favor β-arrestin biased signaling (Murphy, PM. et al. 2000). Indeed, ACKRs behave as scavenging “decoys” in order to either limit chemokines spatial availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand(s) (Nibbs, R. J.; Graham, G. J., 2013). Although less characterized, canonical CKRs have also been shown to not only directly regulate migration but also play a scavenging role (e.g. CCR2, CXCR2, CXCR3, and CX3CR1) (Cardona, A. E., et al. 2008). CCR2 is an example of a dual-function receptor that directly regulates both cell migration and scavenging (Volpe S. et al., 2012), which molecular signature was recently characterized (Shroka, T. M, et al. 2023). This study revealed that CCR2 scavenging is independent of G proteins, GRKs, arrestins, as well as clathrin, which is a different mechanism from what has been established for other chemokine scavenger receptors that where shown to couple to GRKs, β-arrestins, or both such as CCR1. CCR1 is constitutively phosphorylated, constitutively interacts with β-arrestin2, and constitutively internalizes in a β-arrestin2-dependent manner (Gillilan, C. T., et al., 2013). Scavenging allows cells to continuously migrate by remaining responsive to chemokines, it dampens the inflammatory response when needed; and it may interfere with other chemokine receptors which share the ligands and ultimately affect cell migration  (Cardona, A. E., et al. 2008). Interestingly, in monocytes and dendritic cells exposed to treatments mimicking inflammation, CCR1, CCR2, and CCR5 switch purely to scavenging (D'Amico G. et al. 2000), becoming incapable of promoting cell migration, a phenomenon which is likely to be mediated by changes in the cell motility machinery with receptor-specific switches. The scavenging function of CKRs should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand binding. For instance, CCR2 inhibition leads to inhibition of scavenging and elevated plasma levels of CCL2 (Aiello, R. J., et al. 2010), which may ultimately compete with receptor antagonists, thereby decreasing the efficacy. To comprehensively elucidate the role of scavenging in normal physiology and the potential implications of its inhibition, an in-depth understanding of the underlying regulatory mechanisms is needed. Enhancing our knowledge of these regulatory frameworks will provide critical insights into the contribution of scavenging to homeostatic maintenance and the pathological consequences that may arise from its disruption.

Hello everyone! Check out our latest coverage of GPCRs this week, featuring 15 insightful research papers and industry updates. Stay informed with the latest GPCR research and industry news. This week's highlight includes congrats to: Cam Sinh Lu, for his first Dr. GPCR contributor article Extracellular signal-regulated kinases – a potential pathway for GPCR-targeted drug discovery Nicola J Smith, Lauren T May, and Natasha L Grimsey for their work on Highlights and hot topics in GPCR research from 'Down Under' Dr. GPCR University Today marks the final day of the Dr. GPCR University workshop on Advanced Data Analysis for GPCR Pharmacology, led by the esteemed Dr. Sam Hoare. It's been a remarkable experience with participants joining us from around the globe. We're thrilled to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. Stay tuned for more details, and be ready to register in July 2024. Dr. GPCR Podcast We have thrilling news—Episode 153 of the Dr. GPCR Podcast featuring Dr. Jacek Mokrosiński is live! Titled "Embracing Networking for Professional Growth" Our podcast episodes are now available in video format on our website. Revisit your favorite episodes and catch up on any you’ve missed. Tune in and enjoy the visual experience! Dr. GPCR Matchmaking Read Mark's job spotlight article for a Principal Scientist in In Vitro Pharmacology! Mark recently discussed this exciting opportunity with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! GPCR Event Highlight We are delighted to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop will be held in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community and share your research—submit your abstract using this form. We are also seeking sponsors to support this exciting event that unites scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 20th to 26th, 2024. Adhesion GPCRs Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys GPCR Activation and Signaling Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking GRK5 is required for adipocyte differentiation through ERK activation GPCR Binders, Drugs, and more Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists Development of Putative Bivalent Dicovalent Ligands for the Adenosine A1 Receptor GPCRs in Cardiology, Endocrinology, and Taste Sodium/Potassium ATPase Alpha 1 Subunit Fine-tunes Platelet GPCR Signaling Function and is Essential for Thrombosis GPCRs in Oncology and Immunology Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis The EBI2 receptor is coexpressed with CCR5 in CD4+ T cells and boosts HIV-1 R5 replication Methods & Updates in GPCR Research Evaluation and comparison of colorimetric outputs for yeast-based biosensors in laboratory and point-of-use settings Quantitative proteomics reveals CLR interactome in primary human cells Exploiting Cell-Based Assays to Accelerate Drug Development for G Protein-Coupled Receptors TOR signaling regulates GPCR levels on the plasma membrane and suppresses the Saccharomyces cerevisiae mating pathway Reviews, GPCRs, and more Highlights and hot topics in GPCR research from 'Down Under' Apelin receptor dimer: Classification, future prospects, and pathophysiological perspectives Structural and Molecular Insights into GPCR Function Bilayer lipids modulate ligand binding to atypical chemokine receptor 3 Industry News New cannabinoid CB1 receptor antagonists disclosed in Inversago patent Orion Biotechnology will be attending BIO 2024 Antiverse is attending BIO 2024 Septerna to Present Preclinical Data from GPCR Drug Discovery Engine at ENDO 2024 The Promise of Oxytocin: Novel Approaches for Targeting Oxytocin Receptors in Autism Spectrum Disorder and Psychiatric Disorders GPCR Events, Meetings, and Webinars NEW June 1 - 4, 2024 | ENDO 2024 NEW June 3 - 6, 2024 | BIO 2024 June 2 - 7, 2024 | Chemotactic Cytokines June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology NEW Senior Scientist - Receptor Pharmacology NEW PostDoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Join Dr. GPCR Ecosystem

Welcome to the 4th official Adhesion GPCR Consortium newsletter! We welcome suggestions, feedback, and announcements from the community. Announcements Please save the date for the 2024 aGPCR workshop hosted by Antony Boucard! This exciting conference will take place from October 23-25th. We'll see you in Mexico City! Please see this website for details on the conference and the Logo Contest! Member Profile Antony Boucard Professor Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav) How did you become involved in adhesion GPCR research? What is your backstory? AB: I became aware of the existence of adhesion GPCRs while completing my graduate studies. The family of adhesion GPCRs called the Latrophilins or ADGRLs first captured my attention due to their involvement in neuronal synapses uncovered through the mechanism of action of a paralyzing component from black spider venom. For my postdoctoral training, I joined one of the labs that participated in Latrophilins’ discovery, the lab of Dr. Thomas Südhof, but did not start working on them right away. This was because, at that time, the neurexins, another family of adhesion molecules that also happened to be targeted by the same spider toxin as latrophilins, were a more pressing matter. Transitioning to study Latrophilins, I decided to test the interaction of neurexins with Latrophilins. To my surprise and delight, the neurexins happened to be ligands for one isoform of the Latrophilins. Another chapter was being written for me and has been in full redaction since then. What do you think is the next great hurdle in the aGPCR field? What challenges will researchers overcome in the next 10 years? AB: One of the big challenges that the field will have to face in the next 10 years is deciphering the physiological relevance of splice-dependent aGPCR diversity. Alternative splicing events account for hundreds, if not thousands, of potentially divergent isoforms throughout many species. The distribution, functionality, and structure of the multiple splice isoforms that adhesion GPCRs possess are currently unknown. This will greatly impact not only the way we understand how aGPCR works but might also provide a guide to how pharmacological approaches will be developed, i.e., splice isoform-specific agonist/antagonist compounds. How did you become involved with the AGC? Who volunteered you to host the next workshop? AB: I became involved with the AGC through a suggestion from one of my colleagues to join this select group, which was getting together to talk about my favorite molecules. If I wanted to be part of the narrative, I felt that I had to join the community. And so I did. My first meeting was in Boston. I still remember entering the Hall at Boston ́s Children Hospital, going to register and being asked who was my PI. As much as I was shocked that I wasn’t asked if I was a student or a PI, I was more proud to say that I was coming as the founder of my own lab. I was volunteered to host the AGC Workshop by two Board members, Tobias Langenhan and Jörg Hamann. I said yes as soon as they approached me. I, in turn, recruited Yamina Berchiche, founder of DrGPCR.com, to join me in this endeavor. What are you most excited about for the upcoming workshop? If someone is flying in from the other side of the globe, what are three things they must experience in Mexico City? AB: The next workshop will likely bring together some of the hottest adhesion GPCR research going on right now and set the tone for the upcoming years. The excitement I felt when I first attended back in Boston is the same one I feel now that I am the organizer. Also, seeing the expanding diversity among the aGPCR community, added to the fact that this will all take place for the first time in a developing country like Mexico, is paramount. There are a lot of firsts in this perspective: the first time in a LATAM country, the first organized by Afro-descendants (Yamina Berchiche, my co-organizer, has African roots, and my origins are Afro-Carribean). This might not be a big deal for many, but in this new era of making sure that historically excluded demographics are finally included, this represents a building block to reinforce the need for diversity in science. A small step toward leveling the playing field. When in Mexico City from 23-25 October, here is my bucket list of the 3 things that people should absolutely experience: The Day of the Dead celebrations: This happens over the weekend during the end of October and takes the shape of costume parades in which everybody contributes their own versions of the Catarinas (Folklore Mexican ghost lady) or explores the mysterious world of the Alebrijes. Of course, there is the famous parade popularized by the James Bond movie Spectre. The food: While in Mexico, eat like one. The diversity is humongous. No wonder why Mexican cuisine has obtained the coveted status of UNESCO ́s Intangible Cultural Heritage of Humanity. The Teotihuacan Pyramids: although it is very touristy, it is just a hop away from Mexico City and finds its way on many destination lists for a reason. A reminder of how fragile civilizations can be. What is your favorite taco? What mariachi song are you most likely to shout along to at 3 AM? AB: Favorite Taco: Taco de suadero (pronounced swa-day-ro), fatty, with meat caramelized in its own fat, tender, and—oh, did I say fatty? Note that Taco al Pastor is a staple among Mexico City’s delicious tacos. The meat on a rotating spit with its bright red/orange chili-based marinade (spicy but not hot) catches your eye. The way it is served with swiftly chopped charred pineapple for garnish adds to the visuals. A must-try! Mariachi song: I typically do not sing to these since they are dear to Mexican childhood memories, and I feel like an imposter if I do. However, Reggaetón is a highly dynamic genre that attracts many here in Mexico, not to forget salsa music. Don’t be surprised if you find yourself singing Daddy Yankee’s “Gasolina” from the top of your lungs while executing your best perreo or Luis Enrique’s “Yo no sé mañana” while a stranger takes you floating across the dance floor. If this is not the case, go to another party. I know I have. New Insights Members Torsten Schöneberg and Ines Liebscher present an interactive browser-based application, Splice-O-Mat, for understanding tissue distribution of alternatively spliced genes. PMID 38421639 Systematic assessment of the tethered agonist-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation and B-arrestin recruitment assays. PMID: 38608683 The activation profile of different G proteins by ADGRL3 is shown using a collection of biosensor constructs. PMID: 38412860 GPR133 is hypomethylated and upregulated in decidual macrophages in recurrent spontaneous miscarriage patients. PMID: 38564758 BAI1 is expressed in the afferent spiral ganglion neurons in the mouse cochlea where it localizes AMPA receptors at the post-synaptic density and plays a crucial role in sound transmission. PMID: 38564333 CD97 expression is upregulated upon orthodontic compression and inhibits osteoclast differentiation, likely by Rap1a/ERK signaling pathway. PMID: 38311610 Member Dimitris Placantonakis’s identifies extended synaptotagmin 1 as an intracellular interaction partner of GPR133 using proximity labeling. PMID: 38758649 Member Simone Prömel’s lab shows that the nematode (C. elegans) homolog of CELSR, FMI-1, modulates the composition of the ECM and nematode body size. PMID: 38378098 Curated by Sumit J. Bandekar with help from Nathan Zaidman and Abhishek K. Singh

“The desire to take medicine is perhaps the greatest feature which distinguishes man from animals.” Sir William Osler Scientists have long sought to discover a “golden bullet” that would cure every disease without adverse effects. However, the journey to fine-tune human physiology is far from over. The more we know about the pathology of diseases, the more complicated it is to modulate them by a specific pathway without touching others. Notably, G-protein-coupled receptors (GPCRs), representing the biggest drug target, have been revealed to show functions through a plethora of signaling pathways. Historically, drug discovery efforts targeting GPCRs focused on G-protein-dependent signaling pathways, such as those involving cAMP and calcium mobilisation, to identify lead compounds. This emphasis may have caused other signaling pathways to be overlooked due to a need for adequate assay tools. While these signaling pathways are highly interconnected, they can also be regulated independently (Kenakin, 2019). Recent research has unveiled the emergence of G-protein-independent pathways, particularly those involving β-arrestins, which are now proving significant in drug discovery (Wei et al., 2003). β-arrestins, traditionally seen as terminators of G-protein signaling, are now recognised as critical players in activating extracellular signal-regulated kinases (ERK) pathways alongside the G-protein dependent pathways. This dual role opens new possibilities for more complex and nuanced cellular responses. Extracellular signal-regulated kinases (ERK), a subset of the mitogen-activated protein kinase (MAPK) family, have long been known to play a critical role in the signaling pathways of GPCRs. This signaling cascade involves several steps. Initially, the activation of small GTPases like RAS leads to the activation of the MAP kinase kinase kinases (MAPKKKs), such as RAF. RAF then phosphorylates and activates the MAP kinase kinases (MAPKKs), MEK1 and MEK2, which in turn phosphorylate and activate ERK1 and ERK2. Once activated, ERKs translocate to the nucleus, phosphorylating various transcription factors, including ETS, c-Jun, and Fos, modulating gene expression and influencing cellular functions (Lu & Malemud, 2019). ERK signaling, tightly regulated through feedback mechanisms and spatial localisation within the cell, is a crucial determinant of cellular responses such as proliferation, differentiation, migration, survival, growth, growth arrest and apoptosis. The gravity of this regulation becomes even more apparent when we consider the potential consequences of dysregulation. In various pathological conditions, including cancer, aberrant ERK activity can lead to uncontrolled cell proliferation and survival​, highlighting the pressing need to comprehend and control these pathways (Sugiura et al., 2021). ERK activation pathways can be categorised into two main sub-pathways based on their subcellular localisation: nuclear and cytosolic (Volmat & Pouysségur, 2001). The nuclear pathway typically involves ERK translocating into the nucleus to regulate gene expression, while the cytosolic pathway involves ERK acting in the cytoplasm to control other cellular functions. The choice of pathway can result in different cellular responses, underscoring the criticality of precise targeting in drug discovery. This further underscores the need for advanced assay technologies and a deep understanding of cellular signaling. Recently, several high-throughput screening (HTS) assays for ERK activation have been developed, each utilising different detection technologies. These include infrared fluorescence, electrochemiluminescence, fluorescence emission, immunofluorescence staining, HTRF (homogeneous time-resolved fluorescence), and TR-FRET (time-resolved fluorescence resonance energy transfer). Each assay offers unique advantages for detecting ERK activation, contributing to the broader toolkit available for GPCR-related drug discovery (Eishingdrelo & Kongsamut, 2013). In summary, targeting GPCR-activated ERK pathways represents a promising strategy for developing new therapeutics. By understanding the intricacies of GPCR signaling and utilising advanced assay technologies, researchers can identify novel drugs that selectively modulate this specific pathway, improving efficacy and safety profiles in clinical applications. References Eishingdrelo, H., & Kongsamut, S. (2013). Minireview: targeting GPCR activated ERK pathways for drug discovery. Current Chemical Genomics and Translational Medicine, 7, 9. Kenakin, T. (2019). Biased receptor signaling in drug discovery. Pharmacological Reviews, 71(2), 267-315. Lu, N., & Malemud, C. J. (2019). Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone Cell Receptor-Mediated Gene Expression. International Journal of Molecular Sciences, 20(15). Sugiura, R., Satoh, R., & Takasaki, T. (2021). ERK: a double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells, 10(10), 2509. Volmat, V., & Pouysségur, J. (2001). Spatiotemporal regulation of the p42/p44 MAPK pathway. Biology of the Cell, 93(1‐2), 71-79. Wei, H., Ahn, S., Shenoy, S. K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003). Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proceedings of the National Academy of Sciences, 100(19), 10782-10787.

Hello everyone! Make sure you get our latest coverage of GPCRs for this week. We've got 15 insightful GPCR research papers and updates from the industry. Stay informed and up to date with the latest GPCR research and industry news. This week's highlight includes congrats to: John Teye Azietaku for his first contributor article on Illuminating GPCR Research: FRET and BRET-Based Sensors Shed Light on Cellular Signaling Abigail Walker, Aylin Hanyaloglu, et al., for their study on Constitutive internalisation of EP2 differentially regulates G protein signalling Ethan Dintzner, Demet Araç, et al. for their work on The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling Jiankun Lyu, Brian Shoichet, Bryan Roth, et al. for their research on AlphaFold2 structures guide prospective ligand discovery Dr. GPCR University We launched the Dr.GPCR University workshop on Advanced Data Analysis for GPCR Pharmacology led by Dr. Sam Hoare three weeks ago, and it's been fantastic with all the participants from across the world. Mark your calendars for September and October 2024! We are excited to announce that Dr. Terry Kenakin will return with two back-to-back classes. Stay tuned for further details, as we plan to open registrations for both courses in July 2024. Dr. GPCR Podcast Exciting news! Episode 152 with Dr. Arthur Christopoulos is now live, titled "A Brief History of Allosteric Modulators." Dive into this fascinating topic and gain valuable insights from one of the leading experts in the field. Don't miss out—check it out now! And here's something even better: the video versions of our podcast episodes are now available to the public on our website! Re-watch your favorite episodes and catch up on any you have missed. Our most recent episode features our very own Dr. GPCR Board. Tune in and enjoy! Dr. GPCR Matchmaking Meet Mark Schmeizl, our Chief Matchmaker. Whether you’re hiring top talent or seeking a new career opportunity, Mark’s expertise ensures successful matches. Ready to get started? If you're looking to hire, fill out this form. If you want to be hired, fill out this form. And don’t miss our job opportunity spotlight for a Principal Scientist in In Vitro Pharmacology! Mark discussed this position with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! Dr. GPCR Symposia Explore GPCRs with our Premium Membership! Access recorded material from previous events, including the Dr. GPCR Summit editions. Our symposium on Structural Insights into GPCR Activation is postponed. Mark your calendar for the GPCRs as Therapeutic Targets symposium on October 11th, 2024. In the meantime, visit Dr. GPCR Symposia and learn from experts in the field. GPCR Event Highlight We are thrilled to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop, which will be held in vibrant Mexico City from October 23 to 25, 2024. Get ready to share your research with the global GPCR community! Submit your abstract using this form. We are also seeking sponsors to support this exciting event, which unites scientists worldwide to explore all facets of adhesion GPCR biology. If you're interested in sponsoring, please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 13th to 19th, 2024. GPCR Activation and Signaling Constitutive internalisation of EP2 differentially regulates G protein signalling ArreSTick motif controls β-arrestin-binding stability and extends phosphorylation-dependent β-arrestin interactions to non-receptor proteins Identification of Gα12-vs-Gα13-coupling determinants and development of a Gα12/13-coupled designer GPCR GPR160 regulates the self-renewal and pluripotency of mouse embryonic stem cells via JAK1/STAT3 signal pathway A fluorescently-tagged tick kinin neuropeptide triggers peristalsis and labels tick midgut muscles The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling GPCR Binders, Drugs, and more Silicon-Rhodamine Functionalized Evocalcet Probes Potently and Selectively Label Calcium Sensing Receptors In Vitro, In Vivo, and Ex Vivo GPCRs in Neuroscience Novel pharmacological targets for GABAergic dysfunction in ADHD GPCRs in Oncology and Immunology Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis Reviews, GPCRs, and more GPR56, an Adhesion GPCR with Multiple Roles in Human Diseases, Current Status and Future Perspective Structural and Molecular Insights into GPCR Function A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM Antibodies expand the scope of angiotensin receptor pharmacology Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A2A Receptor AlphaFold2 structures guide prospective ligand discovery Industry News Roche reports positive Phase Ib results for its dual GLP-1/GIP receptor agonist CT-388 in people with obesity Septerna to Present Preclinical Data from GPCR Drug Discovery Engine at ENDO 2024 𝐈𝐧𝐭𝐫𝐨𝐝𝐮𝐜𝐢𝐧𝐠 𝐀𝐋𝐋𝐎𝐃𝐃: 𝐀𝐥𝐥𝐨𝐬𝐭𝐞𝐫𝐲 𝐢𝐧 𝐃𝐫𝐮𝐠 𝐃𝐢𝐬𝐜𝐨𝐯𝐞𝐫𝐲 GPCR Events, Meetings, and Webinars May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines NEW June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology NEW Senior Research Associate/Associate Scientist, Protein Science NEW Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Join Dr. GPCR Ecosystem

Human cells express over 800 G-protein-coupled receptors (GPCRs) to facilitate communication with the external environment. These receptors respond to a variety of signals by undergoing structural changes that activate internal G proteins, β-arrestins, and other transducers1. Capturing the dynamics of GPCR activation has always been a challenge because G protein activation in cells occurs in less than a second, reflecting the transient nature of these active states. A recent breakthrough study published in Nature by Makaía M. Papasergi-Scott and colleagues has made significant progress in this area 2. Using time-resolved cryo-electron microscopy (cryo-EM) and variability analysis to monitor the transitions of the Gs protein in complex with the β2-adrenergic receptor (β2AR) at brief sequential intervals following GTP addition, the research team identified the conformational changes that underlie G protein activation and its separation from the receptor. Twenty transition structures generated from overlapping particle subsets along this pathway provide a high-resolution description of the events driving G protein activation upon GTP binding. Unlike previous studies that provided only static snapshots, this approach captures the entire activation sequence in vivid detail. The captured structures reveal a dynamic of conformational changes initiated by the binding of an agonist isoproterenol to β2AR. This interaction significantly increases the receptor’s affinity for GTP, allowing a detailed observation of its interaction with the Gs protein in its activated state. From the initial GTP binding, the structures highlight critical shifts in the α5 helix and the α-helical domain (AHD) of the G protein. These alterations are essential for the complex mechanism of G protein activation, following GTP association with the Gα NTP binding pocket. The activation process begins with the α-helical domain (AHD) of the G protein in an open state, which is crucial for the initial binding of GTP. This early interaction sets the stage for a cascade of significant conformational changes. As GTP stabilizes and migrates towards the P loop, it causes the TCAT motif to shift, a key movement for the subsequent closure of the AHD. Concurrently, the α1 helix extends, propagating structural changes throughout the G protein. Further changes include the movement of Switch II towards the nucleotide-binding pocket and the stabilization of Switch III, both integral to the activation of the G protein. The AHD transitioning to a closed conformation prompts the β2–β3 loop to move away from the α5 helix, disrupting an ionic lock and allowing the α5 helix to start transitioning. This helix undergoes significant restructuring—it breaks and reforms closer to the TCAT motif, which is crucial for the final steps of G protein activation. This detailed process provided by the cryo-EM study offers a clear view of these dynamic states, from an inactive state (open AHD and GTP unbound) to an active state (closed AHD and GTP bound) and ultimately to the dissociation of the G protein from the receptor. This research not only deepens our understanding of a key biological process but also provides a valuable map for pharmaceutical researchers to design new therapies. With this high-resolution, dynamic view of GPCR activation, scientists can better tackle diseases by targeting specific steps within the G-protein activation cycle. This highlights the power of advanced imaging techniques like cryo-EM in solving complex biological puzzles and underscores the importance of understanding cellular processes at the molecular level for therapeutic advancements. Beyond GPCRs, the methods and insights from this study can be applied to other fast, transient biological processes. This approach is valuable for understanding the dynamics of other complex signaling pathways and molecular interactions, offering a deeper understanding of cellular processes at the molecular level. Premont, R. T. & Gainetdinov, R. R. Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69, 511-534 (2007). Papasergi-Scott, M. M. et al. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature (2024).

Hello everyone! Don't miss out on our latest coverage of GPCRs for this week. We have a total of 34 insightful GPCR research papers and seven updates from the industry. Stay informed and up to date with the latest GPCR research and industry news. This week's highlight includes congrats to: Drs. Sara Marsango and Graeme Milligan for their research on the Regulation of the pro-inflammatory G protein-coupled receptor GPR84 Drs. Chakit Arora, J Silvio Gutkind, and Francesco Raimondi for their work on The landscape of cancer-rewired GPCR signaling axes Affiong Ika Oqua, Dr. Alejandra Tomas, et al. for their study on Lipid regulation of the glucagon receptor family Drs. Naveen Thakur, Kenneth A Jacobson, Matthew T Eddy, et al. for their analysis on Membrane mimetic-dependence of GPCR energy landscapes Dr. GPCR University We successfully started our Dr.GPCR University workshop, 'Advanced Data Analysis for GPCR Pharmacology,’ led by Dr. Sam Hoare. Mark your calendar for September and October 2024. Dr. Kenakin will be back with two back-to-back classes. Stay tuned as we plan to open registrations for both classes in July 2024. Dr. GPCR Podcast Episode #151 is out! A special episode with our board, meet Drs. Maria Waldhoer, JoAnn Trejo, and Anne Marie Quinn. Did you watch Episode #150 of the Dr. GPCR Podcast? Join us in this episode to meet the team behind Dr. GPCR, hear anecdotes, and get important announcements. Tune in and be the first to know about the benefits coming your way! Dr. GPCR Matchmaking Mark Schmeizl, our Chief Matchmaker, can help you find your perfect match if you want to hire or be hired. Mark has experience connecting candidates with employers and will work with you to understand your needs and preferences to ensure a successful match. Contact Mark today to get started. Dr. GPCR Symposia Learn more about GPCRs by signing up for a Premium Membership to watch all the material recorded at our previous events, including the three editions of the Dr. GPCR Summit. We have postponed our symposium on Structural Insights into GPCR Activation to a later date. Stay tuned for our next symposium on GPCRs as Therapeutics Targets on October 11th, 2024. In the meantime, visit Dr. GPCR Symposia and learn from experts in the field. GPCR Event Highlight We are thrilled to partner with the Adhesion GPCR Consortium to organize our first Dr. GPCR in-person event. Mark your calendar for October 23 - 25, 2024, as we kick off the 11th Adhesion GPCR Workshop in Mexico City. Abstract submissions and registrations will open soon. Stay tuned We are also looking for sponsors to help support this fabulous event that brings together scientists worldwide working on all aspects of adhesion GPCR biology. Please reply to this email if you'd like to sponsor this event. Let’s dive into the Classified GPCR News from April 29th to May 12th, 2024 Adhesion GPCRs Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses Embryonic spatiotemporal expression pattern of Folded gastrulation suggests roles in multiple morphogenetic events and regulation by AbdA GPCR Activation and Signaling The critical importance of conditions: Reconciling GPCR functionality and biophysical findings Adrenoceptor Desensitization: Current Understanding of Mechanisms Biased agonists of GPR84 and insights into biological control GPR84 in physiology-Many functions in many tissues Regulation of the pro-inflammatory G protein-coupled receptor GPR84 Function and regulation of GPR84 in human neutrophils Large-scale deorphanization of Nematostella vectensis neuropeptide G protein-coupled receptors supports the independent expansion of bilaterian and cnidarian peptidergic systems GPCR Binders, Drugs, and more A relaxin receptor gene RpGPCR41 is involved in the resistance of Rhopalosiphum padi to pyrethroids Discovering allatostatin type-C receptor specific agonists Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model GPCRs in Cardiology, Endocrinology, and Taste The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism Thrombosis With Thrombocytopenia and Post-COVID-Vaccination Syndrome With Anti-G-Protein-Coupled Receptor (GPCR) Antibodies Treated With Therapeutic Plasma Exchange SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes GPCRs in Neuroscience Spatiotemporal organization of prefrontal norepinephrine influences neuronal activity Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons to suppress feeding The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions GPCRs in Oncology and Immunology Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone The orphan G protein-coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor The landscape of cancer-rewired GPCR signaling axes Methods & Updates in GPCR Research ONE-GO: Direct detection of context-dependent GPCR activity Author Correction: GPCR molecular dynamics forecasting using recurrent neural networks Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling Reviews, GPCRs, and more Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures Lipid regulation of the glucagon receptor family Technologies for the discovery of G protein-coupled receptor-targeting biologics Lipid mediators in neutrophil biology: inflammation, resolution and beyond Exploring GPCR signaling pathway networks as cancer therapeutic targets Generation of comprehensive GPCR-transducer-deficient cell lines to dissect complexity of GPCR signaling Structural and Molecular Insights into GPCR Function Membrane mimetic-dependence of GPCR energy landscapes Structural and Computational Insights into Dynamics and Intermediate States of Orexin 2 Receptor Signaling Industry News Addex Gets Creative To Secure Funding And Its Future Reunion Neuroscience Inc. Announces $103 Million Series A Financing Co-Led by MPM BioImpact and Novo Holdings Neurocrine Biosciences Announces Initiation of Phase 1 Clinical Study Evaluating Effects of NBI-1117567 in Healthy Adults Crinetics Pharmaceuticals Reports First Quarter 2024 Financial Results and Provides Business Update Nxera Pharma Operational Highlights and Consolidated Results for the First Quarter 2024 Crinetics Pharmaceuticals To Present Advancements From Atumelnant (Crn04894) And Paltusotine Development Programs At Endo 2024 Exscientia's CEO shares a pipeline overview and learnings from being one of the first AI companies out front and to go public GPCR Events, Meetings, and Webinars May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 July 8 - 10, 2024 | 4th IRN i-GPCRnet Annual October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Post Doctoral Fellow Postdoc Position Principal Scientist, In vitro Pharmacology Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Join Dr. GPCR Ecosystem