Hi there GPCR minds! Join us for a deep dive into the world of GPCRs. This week's highlights: Dr. Terence E. Hébert and their colleagues research on 'G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Collagen Secretion in Myofibroblasts' Dr. Sudarshan Rajagopal and their lab team study on 'Location bias: A "Hidden Variable" in GPCR pharmacology' Yao Lu and colleagues work on 'Molecular insights into orphan GPCRs relevant to schizophrenia' Carole Daly and their team research on 'β-arrestin-dependent and -independent endosomal GPCR activation by the V2.' Save the dates: September 7 - 8: Join the 3rd ECI GPCR Symposium, an event by and for early career investigators in the GPCR field. Register by September 6, 12 pm EST. September 22: Don't miss the Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities'. Share your project with a 1-minute abstract video using this form. Our poster session is now a Kumospace discussion. November 2 - 4: The GPCR Retreat is approaching, and we're proud sponsors! Submit poster abstracts via this form; short talks will be selected. Early-bird registration deadline is September 8, abstract submissions close on October 2, and final registration ends on September 21. Subscribe to Dr. GPCR Newsletter to receive more insights! Now check out the weekly Classified GPCR News from August 21st to 27th, 2023. GPCR Activation and Signaling G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Collagen Secretion in Myofibroblasts β-arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor GPCR Binders, Drugs, and more Altered G-Protein Transduction Protein Gene Expression in the Testis of Infertile Patients with Nonobstructive Azoospermia GPCRs in Neuroscience Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia Re-routing GPR56 signaling using Gα12/13 G protein chimeras GPCRs in Oncology and Immunology Chemokine Cxcl1-Cxcl2 heterodimer is a potent neutrophil chemoattractant Neuroimmune interplay during type 2 inflammation: symptoms, mechanisms and therapeutic targets in atopic diseases Methods & Updates in GPCR Research TrGPCR:GPCR-ligand Binding Affinity Predicting based on Dynamic Deep Transfer Learning Reviews, GPCRs, and more Key Aspects of Modern GPCR Drug Discovery Location bias: A "Hidden Variable" in GPCR pharmacology Structural and Molecular Insights into GPCR Function Structural bioinformatics studies of bacterial outer membrane beta-barrel transporters and their AlphaFold2 predicted water-soluble QTY variants Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain Industry News Superluminal Medicines Launches with $33 Million Seed Round to Fuel its Drug Discovery Engine and Pipeline of Small Molecule Therapeutics Reproducibility of Tanso Biosciences' GPCR Assay GPCR Events, Meetings, and Webinars August 31 - September 1, 2023 | ONCORNET2.0 Final Symposium September 7 - 8, 2023 | 3rd Transatlantic ECI GPCR Symposium September 25 - 28, 2023 | Discovery On Target September 27 - 28, 2023 | Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting NEW February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition NEW March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar NEW March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference NEW April 5 - 10, 2024 | AACR Annual Meeting NEW May 13 - 17, 2024 | 20th Annual PEGS Boston Summit NEW May 16 - 19, 2024 | ASPET 2024 NEW May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition NEW June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Researcher / Senior Researcher in Structural Biology NEW Research Specialist NEW Science Research Writer Postdoctoral Fellow Research Laboratory Specialist Associate Postdoc Research Associate Director, Regulatory Affairs Research Scientist/Senior Scientist I - Molecular Pharmacology Explore Dr. GPCR Ecosystem

Hello readers! Check out the latest advancements in GPCR studies. This week's highlights: Dr. Vladimir Katanaev and colleagues identified compromised GPCR signaling in cancer cells using improved methods for channel capacity estimation. Congrats to the GPCR Therapeutics team for their recent paper in the American College of Clinical Pharmacology! What are you doing September 7-8th? Don't miss the 3rd ECI GPCR 2-day symposium organized by and for early career investigators (ECIs) exploring the fascinating world of GPCRs. Abstract submission for oral presentations closes at 11:30 pm EST today! Abstract submission for poster presentations closes at 11:30 pm EST on August 30, 2023. Registrations close on September 6 at 12pm EST Mark your calendars for September 22nd! We're hosting the Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities'. Share your project in an informal setting with a 1-minute abstract video using this form. Our poster session is now a discussion on Kumospace. The GPCR Retreat is coming up November 2-4! We're proud sponsors of this historic event. Submit poster abstracts using this form; short talks will be selected from submissions. Early-bird registration and abstract submissions close on September 8, and final registration ends on September 21. Hurry! Stay updated with our monthly Dr. GPCR Newsletter! Remember to check out the weekly Classified GPCR News from August 14 to 20, 2023 Adhesion GPCRs Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ( Adgrf1) GPCR Activation and Signaling Single-molecule analysis reveals that a glucagon-bound extracellular domain of the glucagon receptor is dynamic Ligand recognition and G protein coupling of the human itch receptor MRGPRX1 Improved approaches to channel capacity estimation discover compromised GPCR signaling in diverse cancer cells GPCRs in Neuroscience Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens Understanding the Molecular Regulation of Serotonin Receptor 5-HTR1B-β-Arrestin1 Complex in Stress and Anxiety Disorders GPCRs in Oncology and Immunology Exacerbating effects of single-dose acute ethanol exposure on neuroinflammation and amelioration by GPR110 (ADGRF1) activation PAXIP1-AS1 is associated with immune infiltration and predicts poor prognosis in ovarian cancer A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P1 signaling axis Methods & Updates in GPCR Research Magnetic Liposomes Infused with GPCR-Expressing Cell Membrane for Targeted Extraction Using Minimum Organic Solvent: An Investigative Study of Trace THC in Sewage Optogenetic manipulation of Gq- and Gi/o-coupled receptor signaling in neurons and heart muscle cells Structural and Molecular Insights into GPCR Function A method for structure determination of GPCRs in various states Apelin receptor dimerization and oligomerization Molecular Insights into GPCR Mechanisms for Drugs of Abuse Industry News 'GPCR Therapeutics' latest science paper was published by the American College of Clinical Pharmacology Sosei and Cancer Research UK announce first patient dosed with oral immunotherapy drug Trevena Reports Second Quarter 2023 Results and Provides Business Update Crinetics Pharmaceuticals: Paltusotine Phase 3 Data Presented At ENDO Novo Nordisk to Acquire Inversago Pharma GPCR Events, Meetings, and Webinars NEW Antiverse: Reimagining Therapeutic Antibodies Using AI ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) 3rd Transatlantic ECI GPCR Symposium (September 7 - 8, 2023) Discovery On Target - DOT (September 25 - 28, 2023) Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT (September 27 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) MPGPCR Conference (November 15 -17, 2023) ASCEPT Annual Scientific Meeting (November 20 -23, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW PhD Student Position NEW (Junior) Research Associate Protein Science Postdoctoral Fellow Research Laboratory Specialist Associate Postdoc Research Associate Director, Regulatory Affairs Research Scientist/Senior Scientist I - Molecular Pharmacology Director, Clinical Data Management Director, Discovery Toxicology Explore Dr. GPCR Ecosystem

Fine-tuning GPCR signaling: conformational dynamics and intracellular responses GPCR signaling is a complex process modulated by protein conformational states. Following extracellular stimulus detection, receptor activation initiates conformational changes, exposing an intracellular cavity (Kang, Y. et al. 2015, Chen, Q. et al. 2021), that allow interaction with trimeric G proteins, which regulate second messengers like cAMP or Ca2+. While some receptors selectively activate specific G protein families, others are more versatile, yielding diverse responses based on cell-specific G protein expression. Apart from G proteins, GPCRs engage other effectors for signaling modulation. GPCR kinases (GRKs) and β-arrestins are activated by agonist-bound GPCRs and interact with the receptor cavity. Originally recognized for inhibiting G protein signaling, they also influence specific pathways such as MAPK signaling (Song, X. et al. 2009, Coffa, S. et al. 2011). Notably, GRKs phosphorylate active GPCRs, enabling high-affinity arrestin binding, which is crucial for receptor internalization. β-Arrestins facilitate this process by interacting with adapter protein 2 (AP-2) and clathrin. The diversity in GPCR signaling regulation suggests an individualized control mechanism. The "barcode hypothesis" proposes that β-arrestins decode distinct GPCR phosphorylation patterns, which influence their conformational states and functions (Matthees, E. S. F et al. 2021, Chen, H. et al. 2022). Recently, Maharana et al. determined multiple structures of activated b-arrestins in complex with the carboxyl terminus phosphopeptides of different GPCRs using cryo-EM, and discovered a significantly conserved phosphorylation motif in GPCRs that drives b-arrestin interaction and activation (Maharana et al. 2023). While GPCR signaling predominantly occurs at the plasma membrane, certain receptors retain their active conformation during internalization and intracellular trafficking, enabling endocytic signaling. The hypothesis arises that GPCR and β-arrestin-centered effector complexes vary based on subcellular localization, potentially scaffolding distinct signaling platforms. Consequently, understanding dynamic interactions between effectors during trafficking becomes crucial. Despite multifocal signaling, recent studies indicate that signaling occurs within a 100 nm range from the point of origin, suggesting the formation of active "nano domains" in specific membrane niches (Anton, S. E. et al. 2022). Probing GPCR and β-Arrestin conformational states: methods and implications The formation of functional complexes involving GPCRs and β-arrestins hinges on their specific conformational states, influenced by their intricate three-dimensional structures. X-ray protein crystallography yields high-resolution protein structures, illuminating side chain orientations and overall conformational states (Kang, Y. et al. 2015). While it provides precise information, it requires significant protein amounts and suitable crystallization conditions. Cryo-EM, on the other hand, requires less protein and has evolved to achieve resolutions comparable to X-ray crystallography (García-Nafría, J., & Tate, C. G. 2021). Recent years have seen cryo-EM dominate new GPCR structure determinations, offering insight into GPCR-effector complexes. However, both methods struggle with flexible or dynamic regions. Other techniques include nuclear magnetic resonance (NMR) spectroscopy for conformational dynamics analysis context (Park, S. H., & Lee, J. H. 2020, Casiraghi, M. et al. 2019), double electron-electron resonance (DEER) spectroscopy for high-resolution conformational state determination (Wingler, L. M. et al. 2019), and hydrogen-deuterium exchange (HDX) mass spectrometry for time-dependent conformational insights (Komolov, K. E. et al. 2017). Despite their contributions, these methods often lack cellular auxiliary structures and proteins. Emerging strategies incorporate unnatural amino acids and crosslinking for structural data inference in cellular environments. This approach reveals binding interfaces and interactions between GPCRs and β-arrestins, paving the way for capturing challenging protein complexes (Böttke, T., et al. 2020, Aydin, Y. et al. 2023). Moreover, Förster resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), and multi-color fluorescence microscopy assays employ conformation-selective probes for monitoring activation-induced changes in cellular environments (Irannejad, R., et al. 2013). The combination of these diverse methods contributes to a holistic understanding of the intricate dynamics and functions of these signaling proteins. GPCR–β-Arrestin complexes: versatile scaffolding platforms β-arrestins exhibit interactions with over 100 diverse proteins, presenting an array of effectors that could be recruited to GPCR–β-arrestin complexes (Xiao, K et al. 2017). This includes proteins like AP-2 and clathrin, vital for internalization, as well as MAPK cascade kinases which can be activated through specific β-arrestin conformations (Song, X. et al. 2008, Coffa, S. et al. 2011). Notably, β-arrestin isoforms interact distinctively with certain signaling kinases, emphasizing their role as hubs for increasing local effector concentrations near active GPCRs (Perry-Hauser, N. A. et al. 2022). This indicates that the scaffolding role of β-arrestins depends on their conformational state, rearranging to expose specific binding interfaces. Uncovering these interacting effector proteins requires comprehensive and unbiased proteomic datasets. Nevertheless, the diverse functionalities of various GPCRs, coupled with the fluctuating expression of proteins in distinct tissues and cellular environments, introduce challenges to this endeavor. Furthermore, the temporal dynamics of β-arrestin subcellular localization, leading to variations in potential interaction partners, further complicates the comprehensive elucidation of the entire β-arrestin interactome. Recent advancements in experimental and bioinformatics tools offer the potential to explore larger portions of the β-arrestin interactome (Crépieux, P. et al. 2017) although there are several challenges to uncover β-arrestin interactome in all its dimensions. For example, the binding sites for many β-arrestin interaction partners remain elusive, and certain effector proteins with overlapping sites may experience mutually exclusive binding due to steric hindrance (Crépieux, P. et al. 2017). In addition, the question of whether β-arrestin1 and 2 serve overlapping or distinct functions remains, raising the need for more comprehensive protein-protein interaction analyses to uncover connections between the binding partners and diverse cellular processes. Knockout studies in mice suggest that β-arrestin isoforms possess some level of functional redundancy, as depleting one isoform results leads to relatively mild effects (Conner, D. A., et al. 1997, Bohn, L. M. et al. 1999), while dual knockout is lethal (Schmid, C. L., & Bohn, L. M. 2009). However, the evolutionary conservation of both isoforms from fish to mammals indicates their non-redundant roles (Gurevich, E. V., & Gurevich, V. V. 2006). Additionally, not all receptors recruit both isoforms equally and arrestins can undergo different conformational changes for the binding to the same GPCR to mediate differential regulatory effects (Haider, R. S. et al. 2022). Thus, exploring large-scale protein-protein interaction datasets could shed light on connections between β-arrestin isoforms and various cellular processes. Tissue expression levels of β-Arrestins and their implications in cancer In addition to molecular interactions, protein expression levels play a crucial role in determining the formation of protein complexes and their functions within specific tissues (Matthees, E. S. F. et al. 2021). Fine-tuned systems of protein expression regulate various processes, and their imbalance is linked to pathological conditions, including cancer (Gros, R. et al. 2000, Sun, W.-Y. et al 2018). Changes in the availability of regulatory proteins like GRKs can impact GPCR phosphorylation and subsequent β-arrestin binding. Such alterations can also extend to β-arrestin expression levels, potentially affecting the composition and prevalence of GPCR–β-arrestin–effector complexes. By comparing β-arrestin expression data in healthy tissues from the Genotype-Tissue Expression (GTEx) database with data from cancer samples in The Cancer Genome Atlas (TCGA) through the Gene Expression Profiling Interactive Analysis (GEPIA) tool, it is evident that β-arrestin expression is dysregulated in many cancer types. However, β-arrestins do not consistently act as oncogenes or tumor suppressors. In certain cancer types, only one β-arrestin isoform's expression may be altered, while the other remains unchanged. The observed variations in β-arrestin expression likely impact the composition and function of GPCR-mediated downstream signaling complexes, contributing to the complex landscape of cancer-related signaling pathways. Future perspectives In recent years, remarkable strides have been taken in unraveling the intricacies of GPCR signaling and the formation of effector complexes. Innovative structural biology techniques, pharmacological methods, state-of-the-art biosensors, supplementary analyses, including interactome studies and evaluations of tissue-specific expression, have played a pivotal role in identifying essential effector proteins that modulate GPCR functions across both physiological and pathological states. Nonetheless, there is an ongoing need to delve deeper into the intricate mechanisms governing GPCR activation and the assembly of effector complexes. Understanding how specific active conformational states influence the interaction or dissociation of crucial effector proteins within distinct subcellular locations remains a fundamental research question. Ultimately, these efforts hold the promise of unveiling novel insights into cellular signaling and its implications for health and disease. Pinpointing signaling pathways governed by β-arrestins, which exhibit increased or reduced activity within distinct cell types or tissues, will undoubtedly provide valuable guidance for advancing such therapeutic interventions. Check the original article at https://pubmed.ncbi.nlm.nih.gov/37259558/ #GPCR #DrGPCR #Ecosystem

Hello GPCR enthusiasts! Check out the latest advancements in GPCR studies. Save the date! On September 22nd, we're hosting the Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities'. Want to share your project in a casual way? Submit a 1-minute abstract video using this form! We'll be having a discussion session on Kumospace, which is replacing the poster session. The GPCR Retreat is just around the corner! As proud sponsors, we invite you to join us. Submit your abstracts for poster presentation using this form - short talks will be selected from these submissions. Remember, the early-bird registration and Abstract submission deadline is September 8, and the final registration deadline is September 21. We're looking forward to seeing you there! Make sure to stay in the loop with the Dr. GPCR Newsletter! And, don't forget to catch up on the latest Classified GPCR News from August 7 to 13, 2023. GPCR Activation and Signaling Tail engagement of arrestin at the glucagon receptor Gα protein signaling bias at 5-HT1A receptor GPCRs in Cardiology, Endocrinology, and Taste Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity GPCRs in Neuroscience The neuropeptide receptor npr-38 regulates avoidance and stress-induced sleep in Caenorhabditis elegans Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders GPCRs in Oncology and Immunology Molecular characterization of breast cancer cell pools with normal or reduced ability to respond to progesterone: a study based on RNA-seq Reviews, GPCRs, and more Tri-part NanoLuc as a new split technology with potential applications in chemical biology: a mini-review YAP/TAZ: Molecular pathway and disease therapy Primary cilia in skeletal development and disease Industry News Addex Reports 2023 Half Year And Second Quarter Financial Results And Provides Corporate Update Sosei Heptares and Cancer Research UK Announce the Dosing of the First Patient in a Phase I/IIa Trial with Cancer Immunotherapy Drug HTL0039732 Exscientia Business Update for Second Quarter and First Half of 2023 Novo Nordisk to acquire Inversago Pharma to develop new therapies for people living with obesity, diabetes and other serious metabolic diseases X4 Pharmaceuticals Reports Second-Quarter 2023 Financial Results, Provides Corporate Updates, and Reports Emerging Data from Chronic Neutropenia Clinical Program Structure Therapeutics Reports Second Quarter 2023 Financial Results and Recent Highlights GPCR Events, Meetings, and Webinars ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) 3rd Transatlantic ECI GPCR Symposium (September 7 - 8, 2023) Discovery On Target - DOT (September 25 - 28, 2023) Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT (September 27 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) MPGPCR Conference (November 15 -17, 2023) ASCEPT Annual Scientific Meeting (November 20 -23, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Postdoctoral Fellow NEW Research Laboratory Specialist Associate NEW Postdoc Research Associate Director, Regulatory Affairs Research Scientist/Senior Scientist I - Molecular Pharmacology Director, Clinical Data Management Director, Discovery Toxicology Postdoc Fellow - Dr. Robert Lefkowitz Lab Postdoc Fellow - Dr. Robert Lefkowitz Lab Explore Dr. GPCR Ecosystem

Greetings, GPCR fellows! Prepare for the latest GPCR updates. This week's highlights: Dr. Randy Hall's study: GPR37L1's role in shaping cortical astrocytes during development Dr. Nichola J Smith's investigation: Gene expression of TAS1R taste receptors for cardiometabolic disease treatment Drs. Devki D Sukhtankar and Pina M Cardarelli's research: Burixafor Hydrobromide (GPC-100) effects on hematopoietic cells in mice and humans Mark your calendar! The Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities' is set for September 22nd. Want to share your project informally? Submit a 1-minute abstract video using this form. Join us for a discussion session on Kumospace, replacing the poster session. Stay updated with the Dr. GPCR Newsletter for confirmed speaker announcements. Remember to catch up on the Classified GPCR News from July 31st to August 6th, 2023. Adhesion GPCRs Functional partnerships between GPI-anchored proteins and adhesion GPCRs GPCR Activation and Signaling GPCR activation and GRK2 assembly by a biased intracellular agonist Conserved class B GPCR activation by a biased intracellular agonist The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction The relaxin receptor RXFP1 signals through a mechanism of autoinhibition To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 GPCR Binders, Drugs, and more Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors Development of an Affinity-Based Probe to Profile Endogenous Human Adenosine A3 Receptor Expression Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects GPCRs in Cardiology, Endocrinology, and Taste Gene expression analyses of TAS1R taste receptors relevant to the treatment of cardiometabolic disease GPCRs in Neuroscience Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers GPR37L1 controls maturation and organization of cortical astrocytes during development GPCRs in Oncology and Immunology GPCRs and fibroblast heterogeneity in fibroblast-associated diseases Ultrasensitive dose-response for asbestos cancer risk implied by new inflammation-mutation model Methods & Updates in GPCR Research Current and emerging methods for probing neuropeptide transmission Nanowire Biosensors with Olfactory Proteins: Towards a genuine electronic nose with single molecule sensitivity and high selectivity Reviews, GPCRs, and more GPR84 in physiology - many functions in many tissues Bispecific Monoclonal Antibodies in Multiple Myeloma: Data from ASH 2022: A Podcast Structural and Molecular Insights into GPCR Function Structural basis for binding of Drosophila Smaug to the GPCR Smoothened and to the germline inducer Oskar Industry News Addex GABAb Positive Allosteric Modulator Program To Receive Additional Chf 2.7 Million From Indivior In Extended Substance Use Disorder Research Collaboration Addex Therapeutics To Release Half-Year 2023 Financial Results And Host Conference Call On August 10, 2023 X4 Pharmaceuticals Closes $115 Million Loan Facility with Hercules Capital Gene-to-structure and Europe give Proteros customers a winning hand Sosei Heptares Operational Highlights and Consolidated Results for the Second Quarter and First Half of 2023 Septerna: $150 Million Raised To Discover And Advance Novel Oral Small Molecule Medicines Targeting G Protein-Coupled Receptors Novo Nordisk A/S: Semaglutide 2.4 mg reduces the risk of major adverse cardiovascular events by 20% in adults with overweight or obesity in the SELECT trial Crinetics Pharmaceuticals Reports Second Quarter 2023 Financial Results And Provides Corporate Update X4 Pharmaceuticals Announces Industry Veteran Dr. Christophe Arbet-Engels to Join as Chief Medical Officer GPCR Events, Meetings, and Webinars ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) 3rd Transatlantic ECI GPCR Symposium (September 7 - 8, 2023) Discovery On Target - DOT (September 25 - 28, 2023) Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT (September 27 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) MPGPCR Conference (November 15 -17, 2023) ASCEPT Annual Scientific Meeting (November 20 -23, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Director, Regulatory Affairs NEW Research Scientist/Senior Scientist I - Molecular Pharmacology NEW Director, Clinical Data Management Director, Discovery Toxicology Postdoc Fellow - Dr. Robert Lefkowitz Lab Postdoc Fellow - Dr. Robert Lefkowitz Lab Senior Research Specialist - Natural Sciences - Surgery Senior Scientist- Membrane Technologies Explore Dr. GPCR Ecosystem

Welcome, GPCR fellows! Get excited about the latest GPCR news! This week's highlights: Driving Pharma Innovation in Oncology: Domain Therapeutics' Success Proven by Science article. Dr. Terence Hébert’s work on Comparative study on human iPSC-derived vs. rat neonatal cardiomyocytes. Drs. Lukas Grätz, David Gloriam, and Gunnar Schulte’s research on Unveiling pathway selectivity in Frizzleds through conserved micro-switches. Save the date! The upcoming Dr. GPCR Symposium on GPCRs as Therapeutic Modalities is on September 22nd. Want to share your work in an informal setting? Submit a 1-minute abstract video and tell us more about your project using this form. Then, join us on September 22nd for our discussion session, formerly known as The poster session, on Kumospace. Stay tuned by subscribing to the Dr. GPCR Newsletter! We'll be sharing the list of our confirmed speakers soon! In case you missed it, recordings of the Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation are available for premium members to watch anytime. And now let's check out the weekly Classified GPCR News from July 24th to July 30th, 2023. Adhesion GPCRs Dual role of the adhesion G-protein coupled receptor ADRGE5/CD97 in glioblastoma invasion and proliferation. GPCR Activation and Signaling Endosome positioning coordinates spatially selective GPCR signaling. Functions and mechanisms of the GPCR adaptor protein Norbin. G protein-coupled receptor-mediated membrane targeting of PLCγ2 is essential for neutrophil chemotaxis. Monoacylglycerol Lipase Protects the Presynaptic Cannabinoid 1 Receptor from Desensitization by Endocannabinoids after Persistent Inflammation. The role of leucine and isoleucine in tuning the hydropathy of class A GPCRs. Intracellular calcium ion transients evoked by cell poking independently of released autocrine ATP in Madin-Darby canine kidney cells. Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations. GPCR Binders, Drugs, and more Development of a V5-tag-directed nanobody and its implementation as an intracellular biosensor of GPCR signalling. GPCRs in Cardiology, Endocrinology, and Taste Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine. Comparing the signaling and transcriptome profiling landscapes of human iPSC-derived and primary rat neonatal cardiomyocytes. GPCRs in Neuroscience Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus. The Neuromedin U system: pharmacological implications for the treatment of obesity and binge eating behavior. Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex. GPCRs in Oncology and Immunology Interplay between G protein-coupled receptors and nanotechnology. Methods & Updates in GPCR Research Strategies for acquisition of resonance assignment spectra of highly dynamic membrane proteins: a GPCR case study. Structural and Molecular Insights into GPCR Function Ternary model structural complex of C5a, C5aR2, and β-arrestin1. Industry News Omass Therapeutics Celebrates a Series of Recent Publications by their Scientists. Exscientia is the Sniper of the AI Drug Discovery Industry Indivior Announces Q2/H1 2023 Financial Results Scientists Discover a New Way To Develop Drugs Without Side Effects Driving Pharma Innovation in Oncology: Domain Therapeutics' Success Proven by Science Crinetics Hosting Key Opinion Leader Webinar To Discuss The Current Treatment Landscape And Unmet Need In Acromegaly GPCR Events, Meetings, and Webinars ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) NEW 3rd Transatlantic ECI GPCR Symposium (September 7 - 8, 2023) Discovery On Target (September 25 - 28, 2023) ○ NEW Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" (September 27 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) MPGPCR Conference (November 15 -17, 2023) NEW ASCEPT Annual Scientific Meeting (November 20 -23, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs Director, Discovery Toxicology Postdoc Fellow - Dr. Robert Lefkowitz Lab Postdoc Fellow - Dr. Robert Lefkowitz Lab Senior Research Specialist - Natural Sciences - Surgery Senior Scientist- Membrane Technologies Computational Protein Design (GPCR) Explore Dr. GPCR Ecosystem

Welcome, GPCR fellows! Get ready for the latest GPCR news. This week's highlighted papers: Dr. Bryan Roth's work on "Built-in functional selectivity in neurons is mediated by the neuronal protein, GINIP." Dr. Antony Boucard's research on "Biased Signaling is Structurally Encoded As An Autoproteolysis Event in Adhesion G Protein-Coupled Receptor Latrophilin-3/ADGRL3." Gabriele Kockelkoren's contribution as first-author on "Molecular mechanism of GPCR spatial organization at the plasma membrane." Our Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation was a success! Thank you to the speakers and attendees. If you missed it, don't worry. Premium members can always go back and watch the recorded talks at any time. Mark your calendars for the upcoming Dr. GPCR Symposium on GPCRs as Therapeutic Modalities on September 22nd. Interested in chatting about your work in an informal setting? Submit a 1-minute abstract video and tell us more about your project in this form. Stay updated by subscribing to Dr. GPCR Newsletter! Don't forget to check out the weekly Classified GPCR News from July 17th to July 23rd, 2023. Adhesion GPCRs Biased Signaling is Structurally Encoded As An Autoproteolysis Event in Adhesion G Protein-Coupled Receptor Latrophilin-3/ADGRL3. mthl1, a potential Drosophila homologue of mammalian adhesion GPCRs, is involved in antitumor reactions to injected oncogenic cells in flies. GPCR Activation and Signaling Atypical Chemokine Receptor 3 'Senses' CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation. GPCRs in Cardiology, Endocrinology, and Taste Cardiac contraction and relaxation are regulated by distinct subcellular cAMP pools. GPCRs in Neuroscience Mu-opioid receptor selective superagonists produce prolonged respiratory depression. Olanzapine manipulates neuroactive signals and may onset metabolic disturbances. A corazonin G protein-coupled receptor gene in the tick Ixodes scapularis yields two splice variants, each coding for a specific corazonin receptor. GPCRs in Oncology and Immunology A GPCR checkpoint drives CD8+ T cell dysfunction and immunotherapy failure in mice. Methods & Updates in GPCR Research Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2. GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach. Reviews, GPCRs, and more Interplay of thermodynamics and evolution within the ternary ligand-GPCR-G protein complex. Built-in functional selectivity in neurons is mediated by the neuronal protein, GINIP. Structural and Molecular Insights into GPCR Function Molecular mechanism of GPCR spatial organization at the plasma membrane. Industry News Exscientia Initiates Prospective Observational Study in Ovarian Cancer. Domain Therapeutics announces the European Patent Office decision to grant a patent for its proprietary immuno-oncology EP4 receptor antagonist program including DT-9081. Sosei Heptares Acquires Idorsia’s Pharmaceuticals Business in Japan and APAC (ex-China), Accelerating its Transformation into a Fully Integrated Biopharmaceutical Company. Addex Mglu2pam Demonstrates Potential In Substance Use Disorder. Orion Biotechnology Completes Discovery of First-in-Class Molecule Against Undrugged GPCR Target in Four Months Cumulus Oncology and Leadxpro collaborate on small molecules targeting cancer-focused GPCR. GPCR Events, Meetings, and Webinars NEW Summer GPCR Zoominar session (July 27, 2023). ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) Registration ends Tomorrow! Discovery On Target (September 25 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Registration is now open! MPGPCR Conference (November 15 -17, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Director, Discovery Toxicology NEW Postdoc Fellow - Dr. Robert Lefkowitz Lab NEW Postdoc Fellow - Dr. Robert Lefkowitz Lab Senior Research Specialist - Natural Sciences - Surgery Senior Scientist- Membrane Technologies Computational Protein Design (GPCR) Postdoctoral Fellow, Caron Lab Clinical Trial Associate Research Scientist/Senior Scientist I - Molecular Pharmacology Explore Dr. GPCR Ecosystem

Welcome, GPCR enthusiasts! This week's GPCR papers feature a publication by Dr. Robert J Lefkowitz. Join us tomorrow, July 21, in the Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation! The symposium will feature a trainee day with a career panel. Remember to subscribe to Dr. GPCR Newsletter for updates! Check the weekly Classified GPCR News from July 10th to July 16th, 2023. GPCR Activation and Signaling Bias comes in layers. GPCR Binders, Drugs, and more Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models. GPCRs in Cardiology, Endocrinology, and Taste Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia. GPCRs in Neuroscience The head mesodermal cell couples FMRFamide neuropeptide signaling with rhythmic muscle contraction in C. elegans. GPCRs in Oncology and Immunology Ovarian cancer G protein-coupled receptor 1 (OGR1) deficiency exacerbates crystal deposition and kidney injury in oxalate nephropathy in female mice. Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling. Colorectal cancer incidence trends in Golestan, Iran: An age-period-cohort analysis 2004-2018. Methods & Updates in GPCR Research Evaluation of Drug Responses to Human β2AR Using Native Mass Spectrometry. psnGPCRdb: The Structure-network Database of G Protein Coupled Receptors. Reviews, GPCRs, and more Optical approaches for investigating neuromodulation and G Protein-Coupled Receptor signaling. Hijacking of GPCRs and RTKs by pathogens. Structural and Molecular Insights into GPCR Function ALX/FPR2 Activation by Stereoisomers of D1 Resolvins Elucidating with Molecular Dynamics Simulation. The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs. Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase. Industry News Septerna Secures $150 Million in Series B Financing to Advance Pipeline of Novel GPCR-targeted Medicines OMass Therapeutics was shortlisted for ‘Life Sciences and Health Tech Company of the Year’ in the 2023 Thames Valley Tech Awards Sosei Heptares Webinar Presentation for Q2 FY2023 Financial Results Neurocrine Biosciences Announces Appointment of Christine A. Poon to Board of Directors Crinetics Pharmaceuticals Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Confo Therapeutics CEO, Cedric Ververken, will join WuXi AppTec's upcoming online series "BOLD: Innovation That Matters" GPCR Events, Meetings, and Webinars ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) Registration ends Tomorrow! NEW Discovery On Target (September 25 - 28, 2023) 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Registration is now open! NEW MPGPCR Conference (November 15 -17, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Senior Research Specialist - Natural Sciences - Surgery NEW Senior Scientist- Membrane Technologies NEW Computational Protein Design (GPCR) Postdoctoral Fellow, Caron Lab Clinical Trial Associate Research Scientist/Senior Scientist I - Molecular Pharmacology Explore Dr. GPCR Ecosystem

Hello GPCR enthusiasts! We're here to share the latest GPCR news with you. Congratulations to Dr. Graeme Milligan for receiving the Order of British Empire from King Charles III in recognition of his contributions to Biochemical Research and Industry. Don't forget to mark your calendars for July 21st, as the upcoming Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation is quickly approaching! This year's symposium will feature a trainee day with a career panel. If you're interested in presenting a poster, simply fill out the submission form and submit a 1-minute abstract video. Be sure to subscribe to Dr. GPCR Newsletter for updates! Now, let's take a quick look at the Classified GPCR News from July 3rd to July 9th, 2023. GPCR Activation and Signaling G protein activation via chemokine (C-X-C motif) receptor 4 and α1b -adrenoceptor is ligand and heteromer-dependent. The G protein-coupled receptor GPRC5C is a saccharide sensor with a novel "off" response. Mammalian type Opsin 5 preferentially activates G14 in Gq-type G proteins triggering intracellular calcium response. GPCR targeting of E3 ubiquitin ligase MDM2 by inactive β-arrestin. GPCR Binders, Drugs, and more Rational design of highly stabilized and selective adrenomedullin analogs. GPCRs in Cardiology, Endocrinology, and Taste SOCS3 inhibits the mesenchymal stromal cell secretory factor SDF-1-mediated improvement of islet function in non-obese diabetic mice. GPCRs in Neuroscience A bistable inhibitory OptoGPCR for multiplexed optogenetic control of neural circuits. GPCRs in Oncology and Immunology Minireview: functional roles of tissue kallikrein, kinins, and kallikrein-related peptidases in lung cancer. Methods & Updates in GPCR Research Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform. Past, present, and future of tools for dopamine detection. Highly multiplexed bioactivity screening reveals human and microbiota metabolome-GPCRome interactions. Structural and Molecular Insights into GPCR Function Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition. Molecular Dynamics and Machine Learning Study of Adrenaline Dynamics in the Binding Pocket of GPCR. Industry News Dr. Graeme Milligan was awarded the Order of British Empire by King Charles III for services to Biochemical Research and Industry. First Patient Enrolled in Phase 1/2 “ELUCIDATE” Trial Assessing GTAEXS617 in Advanced Solid Tumours A Conversation with Murat Tunaboylu, Antiverse Co-Founder and CEO GPCR Events, Meetings, and Webinars ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) Registration ends Tomorrow! 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Registration is now open! Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Postdoctoral Fellow, Caron Lab NEW Clinical Trial Associate Research Scientist/Senior Scientist I - Molecular Pharmacology Vice President, Medical Affairs Associate Director / Director, Clinical Operations Professor in Cardiovascular Pharmacology Explore Dr. GPCR Ecosystem

Hey there, fellow GPCR enthusiasts! Let's gather 'round for our weekly dose of GPCR News. Congratulations to our Dr. GPCR Partner, Domain Therapeutics, for their nomination of the best-in-class CCR8 antibody candidate, DT-7012. Mark your calendars for July 21st, as the next Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation is fast approaching! The exciting news is that this Symposium will be a trainee day with a career panel. If you want to present a poster, all you have to do is fill out the submission form and submit a 1-minute abstract video. And don't forget to subscribe to Dr. GPCR Newsletter for updates! Let's take a quick look at the weekly Classified GPCR News from June 26th to July 2nd, 2023. Adhesion GPCRs A screen of pharmacologically active compounds to identify modulators of the Adgrg6/Gpr126 signalling pathway in zebrafish embryos. GPCR Activation and Signaling Trans-palmitoleic acid, a dairy fat biomarker, stimulates insulin secretion and activates G protein-coupled receptors with a different mechanism from the cis isomer. Carbon dioxide-induced decrease in extracellular pH enhances the production of extracellular matrix components by upregulating TGF-β1 expression via CREB activation in human dermal fibroblasts. Inverse agonism of lysophospholipids with cationic head groups at Gi-coupled receptor GPR82. A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants. GPCRs in Cardiology, Endocrinology, and Taste Adipocyte G Protein-Coupled Receptors as Potential Targets for Novel Antidiabetic Drugs. GPCRs in Neuroscience Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits. Modulation of GPCR receptors common to gut inflammatory diseases and neuronal disorders, Alzheimer's and Parkinson's diseases as druggable targets through Withania somnifera bioactives: an in silico study. Asymmetric activation of dimeric GABAB and metabotropic glutamate receptors. GPCRs in Oncology and Immunology Dynamic Phosphoproteomics of BRS3 Activation Reveals the Hippo Signaling Pathway for Cell Migration. High expression of GPR50 promotes the proliferation, migration and autophagy of hepatocellular carcinoma cells in vitro. Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gβγ/PKCα/FARP1/Cdc42 axis. Comparative analysis of the occupancy of Histone H3 Lysine 4 methylation in the cells treated with TGFβ and Interferonγ. Esophageal and gastric cancer incidence trends in Golestan, Iran: An age-period-cohort analysis 2004 to 2018. Autocrine proteinase-activated receptor signaling in PC3 prostate cancer cells. Methods & Updates in GPCR Research GPCRana: A web server for quantitative analysis of GPCR structures. Development, synthesis and evaluation of novel fluorescent Endothelin-B receptor probes. Reviews, GPCRs, and more Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes. G protein-coupled receptor-targeting antibody-drug conjugates: Current status and future directions. History and function of the lactate receptor GPR81/HCAR1 in the brain: a putative therapeutic target for the treatment of cerebral ischemia. Comparative analysis of adipokinetic hormones and their receptors in Blattodea reveals novel patterns of gene evolution. Internal and external modulation factors of the orexin system (REVIEW). G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics. Multi-omics integration analysis of GPCRs in pan-cancer to uncover inter-omics relationships and potential driver genes. Structural and Molecular Insights into GPCR Function Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome: in silico protein structure analysis and molecular docking. Structure-based pharmacophore modeling 2. Developing a novel framework for structure-based pharmacophore model generation and selection. Industry News Trevena Announces New Topline OLINVYK Data Highlighting Reduced Cost per Admission from ARTEMIS Real-World Outcomes Study. Sosei Heptares Doses First Subject in Phase I Trial with HTL0048149, a First-in-Class GPR52 Agonist for Schizophrenia. Domain Therapeutics announces nomination of best-in-class CCR8 antibody candidate, DT-7012, further strengthening its unique portfolio of GPCR-targeting immunotherapies. GPCR Events, Meetings, and Webinars NEW ERNEST ECI Zoominar (July 6, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) Registration ends Tomorrow! 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Registration is now open! Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Research Scientist/Senior Scientist I - Molecular Pharmacology NEW Vice President, Medical Affairs NEW Associate Director / Director, Clinical Operations Professor in Cardiovascular Pharmacology Scientist I / Scientist II DOE (Native Mass Spectrometry) Senior Vice President of Global Medical Affairs Postdoctoral Research Associate Explore Dr. GPCR Ecosystem

Welcome, GPCR buffs! Join us for our weekly round-up of GPCR News. Congratulations to our Dr. GPCR Partner, GPCR Therapeutics, for passing the Technology Evaluation process for listing on the KOSDAQ market. Before we dive into the latest news, mark your calendars for July 21st for our next Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation. As we approach the event, we have some news to share: We’ve decided to make this event a trainee day event! We will be hosting a career panel (more on our panelists soon)! We are looking for poster presenters; please fill out the poster submission form. Everyone is welcome to present their work. Please note that you will have to submit a 1-minute abstract video. Stay up-to-date as the program develops by subscribing to our monthly Dr. GPCR Newsletter. Let's review the weekly Classified GPCR News from June 19th to June 25th, 2023. GPCR Activation and Signaling Stimulation of ectopically expressed muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells. Serotonin 5-HT7 receptor slows down the Gs protein: a single molecule perspective. Striatal mGlu5-mediated synaptic plasticity is independently regulated by location-specific receptor pools and divergent signaling pathways. GPCR Binders, Drugs, and more Molecular Characterization of Two Wamide Neuropeptide Signaling Systems in Mollusk Aplysia. Discovery and in vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human PAC1 Receptor. PTK7 is a positive allosteric modulator of GPR133 signaling in glioblastoma. GPCRs in Neuroscience Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with chemotherapy-induced peripheral neuropathy. Methods & Updates in GPCR Research A coiled-coil-based design strategy for the thermostabilization of G-protein-coupled receptors. Reviews, GPCRs, and more 7TM domain structures of adhesion GPCRs: what's new and what's missing? Specialized Pro-resolving Lipid Mediators and Resolution of Viral Diseases. Structural and Molecular Insights into GPCR Function Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y4 Receptor Positive Allosteric Modulator VU0506013. Industry News Data shows nearly 19% weight loss in people with overweight or obesity in Boehringer Ingelheim and Zealand Pharma Phase II trial with survodutide (BI 456906). Sanofi Goes All-In On AI. Inversago Pharma Presents Data from Phase 1b Trial of INV-202, a Peripheral CB1r Blocker for Metabolic Syndrome, at the 83rd American Diabetes Association Scientific Sessions. Octopus 3.0 - Next-Day Turnaround Of Full Plasmid Sequencing Directly From Colonies Indivior to Commence Trading on Nasdaq. GPCR Therapeutics passes the Technology Evaluation process for listing on KOSDAQ. GPCR Events, Meetings, and Webinars Training School on “Cell-based assays to study Adhesion GPCR function" (June 28 - 30, 2023) FREE Seminar Antibodies targeting Membrane Proteins - From Antigen to New Therapeutics (June 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). ONCORNET2.0 Final Symposium (August 31 - September 1, 2023) Registration ends Tomorrow! 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Registration is now open! Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs Professor in Cardiovascular Pharmacology Scientist I / Scientist II DOE (Native Mass Spectrometry) Senior Vice President of Global Medical Affairs Postdoctoral Position in the Gliovascular Unit of Glioblastoma Associate Director / Director, Clinical Operations Postdoctoral Research Associate Explore Dr. GPCR Ecosystem

Chemokine receptors (CKRs) belong to a subfamily of G-protein-coupled receptors (GPCRs) and play a crucial role in inflammation and immune responses. CKRs can be classified into typical CKRs, atypical CKRs (ACKRs) which lack G-protein signaling, and viral CKRs. The chemokine system exhibits great versatility, with more than 50 chemokines interacting with over 20 receptors expressed on various cell types. Thanks to advancements in cryo-electron microscopy (cryo-EM) technology, there has been a rapid increase in the number of experimental structures depicting chemokine receptor-chemokine complexes and revealing the diverse and multifaceted nature of the chemokine receptor system. Currently, there are more than 40 available structures of chemokines and their receptors in the Protein Data Bank (PDB) which reveal common structural features, such as the presence of seven transmembrane domains (TMs 1-7), a bridge between TM7 and the N-terminus (Szpakowska, Bercoff et al. 2014) and a TxP motif in TM2 (Govaerts, Blanpain et al. 2001). A recent comparative analysis study of all structures of CKRs characterizes the molecular recognition processes governing the CKR system providing an overview of the chemokine binding mode and activation mechanisms (Urvas, Lauri & Kellenberger. Esther 2023). Chemokine Binding Mode – from CRS1 to CRS3 Chemokines possess a conserved tertiary structure known as the interleukin 8-like chemokine superfamily which is characterized by a flexible N-terminus, N-loop, three anti-parallel β-strands connected by 30s- and 40s-loops, and a C-terminal α-helix. The subfamily-defining CC/CXC/CX3C/XC motif is located in the N-loop and forms two conserved disulfide bridges, which connect the N-loop to the 30s-loop and the β3-strand, thereby anchoring the distal N-terminus to the core of the chemokine. When comparing the CKRs structures complexes, the disulfide bridges formed between the N-loop and the β3-strand align well, although the position of the disulfide bridges between the N-loop and the 30s-loop varies depending on the subfamily (CC, CXC, or CX3C). The spacing between the cysteine residues in the N-loop determines the subfamily-specific arrangement of the distal N-terminus and the 30s-loop, both of which play a crucial role in the recognition of chemokine receptors. This structural variation may explain why chemokine receptors typically recognize chemokines from only one specific subfamily. Chemokine-CKR interaction follows a common pattern which is generally described by the classic “two-site” model (Crump, Gong et al. 1997) where the chemokine N-loop and β3-strand/40s-loop bind to the receptor N-terminus (CRS1), and the N-terminus assumes diverse binding modes in the 7TM cavity of the receptor (CRS2). These two sites are observed in all typical CKR-chemokine structures. Additionally, other conserved binding features, including CRS1.5 and CRS3, have been identified. CRS1.5 is an intermediate recognition site between CRS1 and CRS2, first described in the CXCR4-vCCL2 structure (Qin, Kufareva et al. 2015), where a proline-cysteine (PC) motif in the receptor N-terminus interacts closely with the N-loop-β3-strand disulfide bridge of the chemokine promoting the chemokine N-terminus orientation towards CRS2 and the receptor N-terminus toward CRS1. The 30s-loop of chemokines can bind either on top of the extracellular loop 2 (ECL2) or inside the major binding pocket, known as CRS3 which is characterized by three different binding modes: CC chemokines with deep binding, CC/CXC chemokines with shallow binding near TM5, and CX3C chemokines with shallow binding near the ECL2 hairpin. CKRs are characterized by a seven transmembrane (7TM) fold structure consisting of three intracellular loops (ICLs 1-3) and three extracellular loops (ECLs 1-3). The N-terminal domains of CKRs has multiple sites for post-translational modifications, including tyrosine sulfation and O-glycosylation (Szpakowska, Fievez et al. 2012, Scurci, Akondi et al. 2021, Verhallen, Lackman et al. 2023), which provide extra negative charges to the N-terminus thereby increasing binding affinity and potency at CRS1. Two conserved disulfide bridges are found in chemokine receptors - one connects the N-terminus to the extracellular tip of the seventh transmembrane helix (TM7) near ECL3, while the other links TM3 with ECL2, which is common to the broader class A GPCR family. The arrangement of the seven transmembrane helices creates a ligand-binding cavity on the extracellular side of the receptor. Activation in Class A GPCRs Ligand binding in the orthosteric site leads to diverse activation mechanisms that converge at the transducer coupling region, resulting in the opening of the intracellular binding site. This involves an outward swing of the intracellular transmembrane helix 6 (TM6) coupled with an inward movement of TM7. Conformational changes between inactive and active states are facilitated by a "microswitch network" composed of conserved sequence motifs which include the W6.48xP6.50 motif and the P5.50I3.40F6.44 motif which are located below the 7TM cavity in the middle of the transmembrane region, and the N7.49P7.50xxY7.53 and D3.49R3.50Y3.51 motifs, located near the intracellular ends of TM7 and TM3, respectively (Weis and Kobilka 2018). All CKRs studied show the canonical active conformation, except CX3CR1 which displays a significantly smaller outward tilt of TM6, and instead TM7 and the intracellular helix 8 move outward from the receptor core to make room for the G-protein (Lu, Zhao et al. 2022). As a result of the unique active conformation, the residues in the microswitch network show non-canonical configurations, indicating the versatility of the GPCR architecture for different activation mechanisms. The road map of CCR5 and CCR2 activation The structure of CCR5 has been studied in complex with various ligands, including endogenous chemokine agonists (CCL5 and CCL3), a chemokine super-agonist ([6P4]CCL5), a chemokine antagonist ([5P7]CCL5), and a small-molecule inverse agonist (maraviroc) (Tan, Zhu et al. 2013, Zheng, Han et al. 2017, Isaikina, Tsai et al. 2021, Zhang, Chen et al. 2021). These structures provide a comprehensive understanding of the mechanisms of agonism and antagonism in chemokine receptor activation. The agonist ligands (CCL5, CCL3, and [6P4]CCL5) bind to the 7TM cavity with their N-termini adopting a hook-like conformation, whereas the chemokine antagonist ([5P7]CCL5) folds into a helical shape due to bulky hydrophobic residues in its proximal N-terminus, resulting in a shallower binding. Common to all four chemokines, the distal N-termini interact with a hydrophobic surface at the bottom of the binding site, while polar interactions formed with specific residues. By examining both the active and inactive states of CCR5, it becomes evident that there are four distinct pathways through which structural alterations in the binding site influence Y2446.44 of the P5.50I3.40Y6.44 motif ultimately driving receptor activation: a) Route 1 - hydrogen bonding to Y2516.51 by CCL3 or CCL5; b) Route 2 - characterized by hydrogen bonding to E2837.39 by A4 of CCL3; c) Route 3 - characterized by steric effects between TM2 and Y3 of CCL5; d) Route 4 - characterized by a deep binding of P3 of [6P4]CCL5. The active state structure of CCR2 with its endogenous agonist CCL2, as well as inactive states with two different small-molecule antagonists have been successfully determined. Comparison between the active and inactive structures reveal conformational shifts that mirror the activation routes 1 and 2 observed in CCR5. Biased Agonism – CCR1 as a model CKR Three active-state structures of CCR1 have been characterized, all of which are bound to a G-protein - two of the structures involve complex formation with endogenous N-terminal truncation variants of CCL15, namely CCL15L (residues 26-92) and CCL15M (residues 27-92), while the third structure lacks a ligand (Shao, Shen et al. 2022). It has been demonstrated that the shorter truncation variant, CCL15L, exhibits bias toward G-protein signaling, which has been structurally related to a conformational change of Y2917.43 tilted toward TM2, a model supported by mutagenesis experiments (Shao, Shen et al. 2022). The structural analysis of CCR1 demonstrates how the interaction or absence of interaction with a specific side chain can dictate whether an agonist exhibits a bias toward G-protein signaling or not, although the precise molecular signature responsible for G-protein activation by CCR1 remains unknown, primarily due to the absence a structure in the inactive state. The Non-canonical Toggle Switch 6.48 - CCR6 as a model CKR The structure of CCR6 bound to CCL20 reveals two significant features at CRS2: a shallow binding mode within the transmembrane binding site and limited interaction with the 7TM bundle. One hypothesis regarding CCR6 activation by CCL20 suggests that the crucial binding feature is the E19845.51–NH2 salt bridge (Nelson, Boyd et al. 2001), with molecular dynamics simulations indicating that the stability of the salt bridge depends on the position of NH2, which is most stable at position 1 (Wasilko, Johnson et al. 2020). The absence of an inactive-state structure of CCR6 makes it challenging to confirm the activation mechanism. However, comparing CCR6 with closely related receptors, CCR7 and CCR9, in their inactive states offers some insights: outward movements of TM3, TM4, and TM6 and an inward movement of TM5 are observed, supporting the hypothesis that CCL20 adjusts the position of TM7 relative to ECL2. These receptors share a glutamine residue at the "toggle switch" position 6.48 and the disruption of a hydrogen-bond network surrounding this non-canonical toggle switch results in the separation of TM3 and TM6 following chemokine binding to the upper part of CRS2. Constitutive Activity of the viral CKR US28 and “Chemokine Scavenger” ACKR3 Both US28 and ACKR3 are constitutively active receptors, meaning they can signal independently of agonist (Casarosa, Bakker et al. 2001, Luker, Steele et al. 2010). US28 evolved high constitutive activity to evade host immunity, whereas ACKR3 functions as a homeostatic chemokine "scavenger" by downregulating extracellular chemokine gradients through constitutive internalization and recycling of chemokines without activating G-protein pathways (Randolph-Habecker, Rahill et al. 2002, Luker, Steele et al. 2010, Tsutsumi, Maeda et al. 2022). Experimental 3D structures of both receptors reveal that they employ distinct mechanisms for constitutive activity. In class A GPCRs, the inactive conformation is stabilized by the inactive configuration of the D3.49R3.50Y3.51motif near the intracellular end of TM3. However, in US28, the factors stabilizing the inactive state of this motif are absent. In addition, it has a glutamate residue at position 3.45, which is not found in human class A GPCRs, and it does not have an acidic residue at position 6.30. These factors make the active state more favorable in US28. In ACKR3, the presence of a tyrosine at position 6.40 plays a role in its constitutive activity (Yen, Schafer et al. 2022) which is also supported by mutagenesis studies (Han, Tachado et al. 2012, Yen, Schafer et al. 2022). However, the role of chemokine ligands in activating US28 and ACKR3 cannot be confirmed without inactive-state structures of these receptors. Recent advancements in cryo-EM technology have led to a rapid increase in the number of experimental structures of chemokine receptors, which provide insights into the complexity of the chemokine system, involving ligand promiscuity within subfamilies, functionally selective biased ligands, and constitutively active and intrinsically biased receptors. As more experimental structures of CKRs continue to emerge, it is expected that a more detailed understanding of chemokine binding and receptor activation will pave the way for significant advancements in the development of therapeutics for a wide range of diseases. Check the original article at https://pubmed.ncbi.nlm.nih.gov/37212620/ #GPCR #DrGPCR #Ecosystem

Greetings GPCR enthusiasts! Join us to explore the fascinating world of GPCRs. This week's GPCR paper features an innovative publication by Dr. Silvio Gutkind. But before we delve into the latest news, we'd like to highlight some upcoming events and resources: Save the date! July 21st marks our next Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation. Check our website frequently for speaker updates. We're also actively seeking speakers and poster presenters for this and future symposiums. Showcase your research by contacting us at Hello@DrGPCR.com Stay informed with Dr. GPCR News by subscribing to our monthly newsletter. Now, let's explore the weekly Classified GPCR News, at a glance from June 12th to June 18th, 2023. GPCR Activation and Signaling Single transmembrane GPCR modulating proteins: neither single nor simple. Structural snapshots uncover a key phosphorylation motif in GPCRs driving β-arrestin activation. CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA. A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants. GPCRs in Neuroscience Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an in silico approach. GPCRs in Oncology and Immunology The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Stimulation of ectopically expressed muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells. Methods & Updates in GPCR Research Spatiotemporal GPCR signaling illuminated by genetically encoded fluorescent biosensors. Industry News Coherus to Acquire Surface Oncology Confo Therapeutics and AbCellera partner on GPCR-targeting antibodies GPCR Inhibition With ICB May Be Needed to Reactivate Antitumor Immune Response Garry Pairaudeau, CTO of Exscientia discuss transforming drug discovery using their AI-driven platform Salipro Biotech Expands Global Intellectual Property Portfolio with Granted Patent in Japan Proteros Biostructures GmbH Revolutionizes Metabolic Disorder Treatments Structure Therapeutics listed on Nasdaq GPCR Events, Meetings, and Webinars NEW FREE ERNEST ECI zoominar (June 22, 2023) NEW Meet Inoviem Scientific Team (June 19 - 23, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) NEW FREE Seminar Antibodies targeting Membrane Proteins - From Antigen to New Therapeutics (June 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Professor in Cardiovascular Pharmacology Scientist I / Scientist II DOE (Native Mass Spectrometry) Senior Vice President of Global Medical Affairs Postdoctoral Position on Gliovascular Unit of Glioblastoma Associate Director / Director, Clinical Operations Postdoctoral Research Associate Explore Dr. GPCR Ecosystem

Hi there GPCR enthusiasts! Join us this week for a deep dive into the world of GPCRs. This week's GPCR papers feature publications from Drs. Ines Liebscher, Ross Cheloha and Silvio Gutkind. Before we dive into this week’s news, we’d like to draw your attention to some of our events and resources: Please mark your calendars for July 21st for our next Dr. GPCR Symposium on Structural and Molecular Insights on GPCR Activation. Our website is updated as we confirm speakers so please check back often. We also seek speakers and poster presenters for the next symposium and beyond! Showcase your work by emailing us at Hello@DrGPCR.com. Stay updated with Dr. GPCR News by subscribing to our monthly newsletter. Our founder Dr. Yamina A. Berchiche is at the Molecular Pharmacology GRC, if you are also on-site, please stop by and say hi. And now let’s dive into the weekly Classified GPCR News at a glance for June 5th to June 11th, 2023. Adhesion GPCRs Collagen VI Is a Gi-Biased Ligand of the Adhesion GPCR GPR126/ADGRG6. Hexahydroquinoline Derivatives are Selective Agonists for the Adhesion G Protein-Coupled Receptor ADGRG1/GPR56. GPCR Activation and Signaling Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome Antagonistic interactions between odorants alter human odor perception. Autocrine Proteinase-Activated Receptor (PAR) signaling in PC3 prostate cancer cells. Statin-induced increase in actin polymerization modulates GPCR dynamics and compartmentalization. Class B1 GPCR activation by an intracellular agonist. The G protein-coupled receptor neuropeptide receptor-15 modulates larval development via the transforming growth factor-β DAF-7 protein in Caenorhabditis elegans. GPCR Binders, Drugs, and more Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA. GPCRs in Cardiology, Endocrinology, and Taste Discovery of paralogous GnRH and corazonin signaling systems in an invertebrate chordate. GPCRs in Neuroscience Early pheromone perception remodels neurodevelopment and accelerates neurodegeneration in adult C. elegans. Methods & Updates in GPCR Research A Peptidisc-based Survey of the Plasma Membrane Proteome of a Mammalian Cell. Reviews, GPCRs, and more Diversification processes of teleost intron-less opsin genes. Regulation of the length of neuronal primary cilia and its potential effects on signalling. Structural and Molecular Insights into GPCR Function Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84. Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314. GPCRs in Immunology and Oncology The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure Industry News X4 Pharmaceuticals Expected to Join Russell 3000® Index. Novartis bolsters innovative medicines strategy and renal pipeline with agreement to acquire Chinook Therapeutics for USD 3.2bn upfront (USD 40 / share). EyeBio Announces First Patients Dosed in Phase 1b/2 Trial of Restoret™ in Neovascular Age Related Macular Degeneration and Diabetic Macular Edema. Confo Therapeutics Enters Into Research Collaboration For GPCR-Targeting Antibody Discovery With AbCellera. GPCR Events, Meetings, and Webinars GPCRs in drug discovery: challenges & solutions (June 19 - 23, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) NEW Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Scientist I / Scientist II DOE (Native Mass Spectrometry) Senior Vice President of Global Medical Affairs Postdoctoral Position on Gliovascular Unit of Glioblastoma Associate Director / Director, Clinical Operations Postdoctoral Research Associate Lab Manager Explore Dr. GPCR Ecosystem

Hello GPCR friends👋, Stay informed with the latest developments in GPCR research and industry news! Happy reading📚! This week, we would like to highlight two new publications: Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics. Tagged for arrest: 'Barcode' determines receptor's fate. Our next Dr. GPCR Symposium is coming up on July 21st on Structural and Molecular Insights on GPCR Activation. We are looking for speakers and poster presenters! If you'd like to showcase your work, please email us at Hello@DrGPCR.com. For more information, follow the Dr. GPCR News by subscribing to our monthly newsletter. We look forward to seeing you in a few days at the Molecular Pharmacology GRC and the associated Molecular Pharmacology GRS in Switzerland. We would also like to take a moment to thank the organizers for inviting Dr. Yamina Berchiche, our founder. Below is your Classified GPCR News at a glance for May 29th to June 4th, 2023. GPCR Activation and Signaling Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief. Molecular mechanism of fatty acid activation of FFAR1. Conformational flexibility of β-arrestins - How these scaffolding proteins guide and transform the functionality of GPCRs. Gβγ signaling regulates microtubule-dependent control of Golgi integrity. Ligand-dependent intracellular trafficking of the G protein-coupled P2Y6 receptor. GPCR Binders, Drugs, and more ACE2 Activation by Tripeptide IRW (Ile-Arg-Trp) Depends on the G Protein-Coupled Receptor 30 Signaling Cascade. Molecular insights into peptide agonist engagement with the PTH receptor. An Atomic Level Investigation of Sodium Ions Regulating Agonist and Antagonist Binding in the Active Site of a Novel Target 5HT2BR Against Drug-Resistant Epilepsy. GPCRs in Cardiology, Endocrinology, and Taste GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy. Bitter Odorants and Odorous Bitters: Toxicity and Human TAS2R Targets. GPCRs in Neuroscience DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons. The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits. The crosstalk between 5-HT2AR and mGluR2 in schizophrenia. GPCRs in Oncology and Immunology A2aR on lung adenocarcinoma cells: A novel target for cancer therapy via recruiting and regulating tumor-associated macrophages. Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux. CircFKBP5 Suppresses Apoptosis and Inflammation and Promotes Osteogenic Differentiation. Transcriptomic analysis of human cytomegalovirus to survey the indirect effects on renal transplant recipients. Pharmacological inhibition of neuropeptide Y receptors Y1 and Y5 reduces hypoxic breast cancer migration, proliferation, and signaling. Methods & Updates in GPCR Research Illuminating the brain-genetically encoded single wavelength fluorescent biosensors to unravel neurotransmitter dynamics. Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes. Structure-based pharmacophore modeling 1. Automated random pharmacophore model generation. NMR applications to GPCR recognition by peptide ligands. How can we improve the measurement of receptor signaling bias? Reviews, GPCRs, and more Advancements in G protein-coupled receptor biosensors to study GPCR-G protein coupling. Application of computational methods for class A GPCR Ligand discovery. New paradigms in purinergic receptor ligand discovery. Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins. Lysophosphatidic acid, a simple phospholipid with myriad functions. Structural and Molecular Insights into GPCR Function Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics. The role of G protein conformation in receptor-G protein selectivity. Components of TOR and MAP kinase signaling control chemotropism and pathogenicity in the fungal pathogen Verticillium dahliae. New insights into GPCR coupling and dimerisation from cryo-EM structures. Computational insights into ligand-induced G protein and β-arrestin signaling of the dopamine D1 receptor. Understanding the Rhodopsin Worldview Through Atomic Force Microscopy (AFM): Structure, Stability, and Activity Studies. Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis. Industry News Structure Therapeutics Announces Poster Presentations of its Oral GLP-1 Receptor Agonist GSBR-1290 at the American Diabetes Association 83rd Scientific Sessions Domain Therapeutics' Nomination of DT-9045: A Groundbreaking NAM for Immunooncology Structure Therapeutics to Present at Jefferies Healthcare Conference Tagged for arrest: “Barcode” determines receptor’s fate. GPCR Events, Meetings, and Webinars FREE Symposium - IPI Surfacing (June 15, 2023) GPCRs in drug discovery: challenges & solutions (June 19 - 23, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Retreat (November 2 - 4, 2023) GPCR Jobs NEW Senior Vice President of Global Medical Affairs NEW Postdoctoral Position on Gliovascular Unit of Glioblastoma Associate Director / Director, Clinical Operations Postdoctoral Research Associate Lab Manager Vice President, Medical Affairs Explore Dr. GPCR Ecosystem

Hi GPCR lovers👋, Ready for exciting news in the GPCR world? Read them below! You can now watch the live talk recordings from the previous symposiums, check them out here. Also, let's congratulate Lauri Urvas on his first first-author paper! Check out GPCR papers featuring Drs. Bryan Roth, Peter Gmeiner, and Thomas P. Sakmar this week. For Dr. GPCR News, please subscribe to our monthly newsletter. Below is your Classified GPCR News at a glance for May 22 to 28, 2023. GPCR Activation and Signaling The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. Multiple Subthreshold GPCR Signals Combined by the G-Proteins Gαq and Gαs Activate the Caenorhabditis elegans Egg-Laying Muscles. Modulating GPCR and 14-3-3 protein interactions: prospects for CNS drug discovery. GPCR Binders, Drugs, and more Design of Drug Efficacy Guided by Free Energy Simulations of the β2 -Adrenoceptor. Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells. Differential Responses of the GLP-1 and GLP-2 Receptors to N-Terminal Modification of a Dual Agonist. GPCRs in Cardiology, Endocrinology, and Taste Pathophysiology and pharmacology of G protein-coupled receptors in the heart. GPCRs in Neuroscience PACAP key interactions with PAC1, VPAC1, and VPAC2 identified by molecular dynamics simulations. Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief. Structural and Molecular Insights into GPCR Function Cholesterol Biases the Conformational Landscape of the Chemokine Receptor CCR3: A MAS SSNMR-Filtered Molecular Dynamics Study. The intertwining roles of caveolin, oxytocin receptor, and the associated signalling pathways in prostate cancer progression. A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes. Divergent regulation of α-arrestin ARRDC3 function by ubiquitination. Molecular mechanism of fatty acid activation of FFAR1. Structural genomics of the human dopamine receptor system Structural Insights into Molecular Recognition and Receptor Activation in Chemokine–Chemokine Receptor Complexes Industry News Mavorixafor reduces infection rates among patients with WHIM syndrome Bristol Myers Squibb’s Investigational LPA1 Antagonist Reduces the Rate of Lung Function Decline in Patients with Idiopathic Pulmonary Fibrosis Exscientia Business Update for First Quarter 2023 Structure Therapeutics Initiates Phase 2a Study of Oral GLP-1 agonist GSBR-1290 for the Treatment of Type 2 Diabetes and Obesity Prof. Andrew Hopkins, Exscientia's CEO, will speak at the University of Chicago's Distinguished Seminar Series on Population and Precision Health next week. Your body naturally produces opioids without causing addiction or overdose – studying how this process works could help reduce the side effects of opioid drugs GPCR Events, Meetings, and Webinars The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) NEW GPCRs in drug discovery: challenges & solutions (June 19 - 23, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) NEW GPCR Retreat (November 2 - 4, 2023) GPCR Jobs NEW Associate Director / Director, Clinical Operations Postdoctoral Research Associate Lab Manager Vice President, Medical Affairs Associate Scientist - Technology Explore Dr. GPCR Ecosystem

At the cellular level, the plasmatic membrane is a thin layer of lipids that surrounds the entire cell allowing the differentiation between the intracellular and extracellular environment. The physical barrier this lipid bilayer creates is dynamic and interactive, becoming the foundation for many interactions involved in GPCR signaling6. The cellular membrane's composition, organization, and physical properties might impact ligand binding, receptor activation, G protein interactions, signaling dynamics, and signal termination, highlighting the importance of studying their role in the activation of GPCRs2. β-arrestins are cytosolic proteins that translocate to the plasma membrane upon GPCR activation, then regulate trigger receptor internalization via interaction with the adaptor protein 2 (AP2) and clathrin heavy chain mediating G protein-independent effects. At this point, the lipid bilayer serves as a platform for the membrane recruitment of β-arrestins. Lipid molecules, such as phosphoinositides, can bind to specific domains of β-arrestins, promoting their association with the plasma membrane. Therefore the lipid composition of the bilayer can influence the kinetics and efficiency of β-arrestin recruitment to the membrane, regulating their interactions with activated GPCRs2-6. Understanding the interplay between GPCRs and β-arrestins and how this complex operates on the plasma membrane of living cells was the goal achieved by Jak Grimes et al. Based on an ingenious combination of multicolor single-molecule microscopy approach with molecular dynamics simulations, they dissected the sequence of events in receptor-β-arrestin interactions at the plasma membrane of living cells with ~20 nm spatial and ~30 ms temporal resolution. Whit this scope, the authors challenged the current model, wich suggest that β-arrestin translocates from the cytosol to bind an active receptor on the plasma membrane directly and remains attached to the same receptor until they reach clathrin-coated pits (CCPs)1. However, the evidence obtained in this study proposes novel molecular mechanisms in which β-arrestin exhibits spontaneous pre-association with the plasma membrane. This pre-association enables β-arrestin to explore its surroundings through lateral diffusion and engage in highly transient interactions with receptors, ultimately leading to β-arrestin activation. This event extends the duration of β-arrestin at the plasma membrane, enabling it to independently reach clathrin-coated pits (CCPs) without solely relying on the initial and short-lived receptor-β-arrestin complexes 1. Based on all the information collected, the authors proposed the following multistep model for receptor-β-arrestin interactions under unstimulated and stimulated conditions: Unstimulated condition: Inactive β-arrestin in the cytosol spontaneously binds to the plasma membrane by inserting the C-edge into the lipid bilayer, allowing it to explore space via lateral diffusion. Most β-arrestin molecules remain on the plasma membrane briefly before dissociating and returning to the cytosol. Stimulated condition in the presence of a stimulated receptor: Spontaneous insertion into the plasma membrane β-arrestin. β-arrestin reaches the receptor via lateral. Transient interaction with the receptor catalyzes β-arrestin activation, including β-arrestin inter-domain rotation and extension of the finger loop. Following dissociation from the receptor, the interaction of the extended finger loop with the lipid bilayer likely contributes to stabilizing β-arrestin in a membrane-bound, active-like conformation. The above causes β-arrestin molecules to stay longer and accumulate on the plasma membrane, allowing them to reach CCPs vial lateral diffusion separately from the activating receptors. The increase in active β-arrestin molecules and the time they spend diffusing on the plasma membrane leads to their recruitment and accumulation in CCPs via interaction with AP2 and clathrin. β-arrestin molecules tethered to CCPs bind receptors diffusing on the plasma membrane, also causing their recruitment and accumulation in CCPs. Although this study has limitations, such as the absence of the flexible distal C-tail of βArr2 in the model used, its findings redefine the existing model of receptor-β-arrestin interactions. They shed light on the essential role of β-arrestin binding to the lipid bilayer for efficient interaction between β-arrestin and the receptor. Read the complete article here: https://www.ecosystem.drgpcr.com/gpcr-binders-drugs-and-more/in-depth-molecular-profiling-of-an-intronic-gnao1-mutant-as-the-basis-for-personalized-high-throughput-drug-screening References Grimes, J., Koszegi, Z., Lanoiselée, Y., Miljus, T., O'Brien, S. L., Stepniewski, T. M., Medel-Lacruz, B., Baidya, M., Makarova, M., Mistry, R., Goulding, J., Drube, J., Hoffmann, C., Owen, D. M., Shukla, A. K., Selent, J., Hill, S. J., & Calebiro, D. (2023). Plasma membrane preassociation drives β-arrestin coupling to receptors and activation. Cell, 186(10), 2238–2255.e20. https://doi.org/10.1016/j.cell.2023.04.018 Janetzko, J., Kise, R., Barsi-Rhyne, B., Siepe, D. H., Heydenreich, F. M., Kawakami, K., Masureel, M., Maeda, S., Garcia, K. C., von Zastrow, M., Inoue, A., & Kobilka, B. K. (2022). Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics. Cell, 185(24), 4560–4573.e19. https://doi.org/10.1016/j.cell.2022.10.018 Latorraca, N.R., Wang, J.K., Bauer, B., Townshend, R.J.L., Hollingsworth, S.A., Olivieri, J.E., Xu, H.E., Sommer, M.E., and Dror, R.O. (2018). Molecular mechanism of GPCR-mediated arrestin activation. Nature 557, 452–456. https://doi.org/10.1038/s41586-018-0077-3 Pierce, K.L., and Lefkowitz, R.J. (2001). Classical and new roles of b-arrestins in the regulation of G-protein-coupled receptors. Nat. Rev. Neurosci. 2, 727–733. https://doi.org/10.1038/35094577. Reiter, E., Ahn, S., Shukla, A.K., and Lefkowitz, R.J. (2012). Molecular mechanism of b-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev. Pharmacol. Toxicol. 52, 179–197. https://doi.org/10. 1146/annurev.pharmtox.010909.105800 Tsao, P. I., & von Zastrow, M. (2001). Diversity and specificity in the regulated endocytic membrane trafficking of G-protein-coupled receptors. Pharmacology & therapeutics, 89(2), 139–147. https://doi.org/10.1016/s0163-7258(00)00107-8

Hi GPCR buffs 👋! This week's GPCR papers feature a publication from Dr. Marta Filizola. Check it out! The Dr. GPCR Symposium on GPCR Activation and Signaling was a great success. We express our gratitude to the speakers for their excellent talks. Our next symposium is on July 21st, 2023, focusing on Structural and Molecular Insights into GPCR Activation. If you are interested in giving a talk, contact us at Hello@DrGPCR.com, and if you would like to present a poster, submit this form here. Take the chance to contribute to this exciting event! For Dr. GPCR News, please subscribe to your monthly newsletter. Below is your Classified GPCR News at a glance for May 15th to 21st, 2023. GPCR Activation and Signaling Monitoring the Reversibility of GPCR Signaling by Combining Photochromic Ligands with Label-free Impedance Analysis. FSLLRY-NH2, a protease-activated receptor 2 (PAR2) antagonist, activates mas-related G protein-coupled receptor C11 (MrgprC11) to induce scratching behaviors in mice. ACE2 Activation by Tripeptide IRW (Ile-Arg-Trp) Depends on the G Protein-Coupled Receptor 30 Signaling Cascade. Gαs slow conformational transition upon GTP binding and a novel Gαs regulator. GPCRs in Neuroscience Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors. A vital role for PICK1 in the differential regulation of metabotropic glutamate receptor internalization and synaptic AMPA receptor endocytosis. GPCRs in Oncology and Immunology Stable Binding of Full-Length Chemerin is Driven by Negative Charges in the CMKLR1 N-terminus. Methods & Updates in GPCR Research Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis. Reviews, GPCRs, and more Analysis of the Dynamics of the Human Growth Hormone Secretagogue Receptor Reveals Insights into the Energy Landscape of the Molecule. Industry News X4 Pharmaceuticals Announces $65 Million Private Placement Priced At-the-Market Andrew Hopkins, Exscientia’s founder and CEO was elected a Fellow of the Academy of Medical Sciences Structure Therapeutics Announces Poster Presentations at the American Thoracic Society International Conference GPCR Events, Meetings, and Webinars SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) PEGS Boston (May 15 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs NEW Postdoctoral Research Associate NEW Lab Manager Vice President, Medical Affairs Associate Scientist - Technology Senior Research Scientist/Principal Scientist- Technology Tissue Culture Scientist/Tissue Culture Manager Postdoctoral Researcher Director - Targeted Oncology Explore Dr. GPCR Ecosystem

Hi GPCR lovers! Stay tuned for the latest buzz on GPCRs. This week's GPCR papers feature publications from Drs. Vladimir Katanaev and Patrick Sexton. Remember to join us tomorrow, May 19th, for the highly anticipated Dr. GPCR Symposium on GPCR Activation and Signaling! If you're interested in presenting a poster, there's still time. Simply submit your information using this form. To receive our monthly newsletter, please subscribe to Dr. GPCR News. Below is your Classified GPCR News at a glance for May 8th to 14th, 2023. GPCR Activation and Signaling Ligand-induced activation and G protein coupling of prostaglandin F2α receptor. Plasma membrane preassociation drives β-arrestin coupling to receptors and activation. Gβγ activates PIP2 hydrolysis by recruiting and orienting PLCβ on the membrane surface. GPCR Binders, Drugs, and more In-depth molecular profiling of an intronic GNAO1 mutant as the basis for personalized high-throughput drug screening. An allosteric modulator of the adenosine A1 receptor potentiates the antilipolytic effect in rat adipose tissue. GPCRs in Cardiology, Endocrinology, and Taste Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications. GPCRs in Oncology and Immunology DANGER Signals Activate G-Protein Receptor Kinases Suppressing Neutrophil Function and Predisposing to Infection After Tissue Trauma. Reviews, GPCRs, and more Recent Studies on Serotonin 5-HT2A Receptor Antagonists in Medicinal Chemistry: A Last Decades Survey. Mechanism of Activation of the Visual Receptor Rhodopsin. The application of artificial intelligence to accelerate GPCR drug discovery. Structural and Molecular Insights into GPCR Function New Insights into the Structure and Function of Class B1 GPCRs. Industry News InterAx Biotech to Apply its Leading AI and Cell Signalling Technology to Support Target Validation for a Sosei Heptares GPCR Discovery Program Salipro Biotech and DyNAbind Announce Milestone Achievement in Collaboration to Enable DEL for Membrane Proteins Professor Andrew Hopkins, Exscientia’s founder and CEO, was elected as a Fellow of the The Royal Society. Addex Announces ADX71149 Phase 2 Epilepsy Clinical Study’s Independent Interim Review Committee Recommends Continuing Study Addex Therapeutics in the 23rd BioEquity Europe Conference Simon Bekker-Jensen and Mette M Rosenkilde received two proof of concept grants from European Research Council (ERC) Addex Reports Q1 2023 Financial Results And Provides Corporate Update Structure Therapeutics Reports First Quarter 2023 Financial Results and Recent Highlights OMass Therapeutics presented at the 23rd BioEquity Conference British Patient Capital Invests £10m in next-generation drug development company OMass Therapeutics Sosei Heptares 2022 ESG report Exscientia Announces Sixth Molecule Created Through Generative AI Platform to Enter Clinical Stage X4 Pharmaceuticals Announces Positive Phase 3 Results Showing Mavorixafor Reduced the Rate, Severity, and Duration of Infections vs. Placebo in Participants Diagnosed with WHIM Syndrome GPCR Events, Meetings, and Webinars ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) PEGS Boston (May 15 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs Vice President, Medical Affairs Associate Scientist - Technology Senior Research Scientist/Principal Scientist- Technology Tissue Culture Scientist/Tissue Culture Manager Postdoctoral Researcher Director - Targeted Oncology Senior Scientist - Antibody Engineering Scientist—Immuno-Oncology Convergent Research - Senior Scientist, Cell-Based Assay Development Explore Dr. GPCR Ecosystem

Artificial intelligence - Machine learning vs Deep Learning GPCRs have long been recognized as important drug targets, and numerous drugs that modulate GPCRs are already in clinical use for various diseases. The integration of AI in GPCR drug discovery has the potential to accelerate the identification and development of novel drugs, optimize drug design processes, and enhance the understanding of GPCR biology. High-throughput approaches used in drug discovery create large datasets regarding ligand synthesis and screening, ligand binding assays, signaling assays, cell imaging, protein structure determination, and omics applications, which can be analyzed by an established AI framework which involves three stages: 1) feature extraction or pattern identification; 2) vector space construction and metric definition where data is classified and compared; and 3) detection, prediction, or generation (e.g. prediction of a protein structure, or ligand design). Machine learning (ML) and deep learning (DL) are subfields of artificial intelligence (AI) that involve training algorithms to learn from data. While they share similarities, there are notable differences in respect to neural network architecture, complexity, data requirements, training time, computational resources and interpretability. ML algorithms typically use traditional ML models, such as decision trees and support vector machines which require handcrafted feature engineering, where domain experts manually select and engineer relevant features from the input data. While classical ML models are effective for datasets for which the relevant features are well understood, their use for datasets for which the relevant features of the input data are unknown, such as in drug discovery, is limited - the solution is DL. DL algorithms employ artificial neural networks with multiple layers of interconnected nodes which learn hierarchical representations of the data, eliminating the need for explicit feature engineering and allowing the exploitation of features that would not typically occur using classical ML algorithms. However, DL algorithms typically require large amounts of labelled training data comprising millions of parameters, becoming infeasible for a human to interpret, in contrast with alternative ML models which comprise handcrafted features and simpler models. For this reason, DL models generally require more computational resources (such as powerful GPUs) and longer training times. Artificial intelligence in GPCR drug discovery The use of AI in GPCR drug discovery has increased over the last decade and is revolutionising the way new GPCR-targeted drugs are developed. AI is providing a dramatic acceleration of the drug discovery process at multiple stages: 1. Classification: AI models can be used to distinguish GPCRs from non-GPCRs, and to classify GPCRs into families, subfamilies, sub-subfamilies, and subtypes. The models use a variety of data for the input, including amino acid sequences or structural data (from X-ray crystallography, cryoEM or molecular dynamics simulation experiments). 2. Mutations: ML methods can determine stabilising mutations that enable structure determination and can also predict the effect of mutagenesis on GPCR function. 3. Structure: the development of algorithms such DeepMind’s Alphafold2 (Jumper et al., 2021) and RoseTTAFold (Baek et al., 2021) allow the prediction of the 3D structure of a protein from the amino acid sequence even where no similar structure is known. 4. GPCR-ligand interactions: ML can predict GPCR-ligand interactions based on input data of protein sequences and molecular fingerprints coming from databases such as the GPCR-Ligand Association (GLASS), bindingDB and DrugBank. One major challenge is the identification of receptor subtype-selective ligands. In this context, BRS-3D was used to predict subtype-selective ligands for dopamine receptors and adenosine receptors (He, Ben, Kuang, Wang & Kong, 2016; Kuang, Feng, Hu, Wang, He & Kong, 2016). 5. Virtual screening: molecular docking and virtual screening can efficiently analyze large databases of compounds and predict their binding affinity to GPCRs, aiding the identification of lead compounds for further development. Paremeters such as ligand affinity for the receptor (pKi), the ability of a ligand to induce or inhibit a cellular response (pEC50 or pIC50, respectively), and how long the ligand remains bound to the receptor (koff), are used to short-list candidate drugs for further assessment. 6. De novo drug design: AI algorithms can generate new molecules with desired properties, such as binding affinity and selectivity to specific GPCRs. 7. Predicting GPCR properties: AI models can predict various properties of GPCRs, such as ligand binding sites (orthosteric, allosteric), activation mechanisms, and conformational changes. 8. Multi-target drug design: GPCRs are often involved in complex signaling networks. AI algorithms can integrate data from multiple sources, including genomics, proteomics, and pharmacological data, to identify potential drug targets within the GPCR signaling pathways. 9. Side effect prediction and clinical responses: AI can predict potential off-target effects and adverse drug reactions associated with GPCR-targeted drugs. With the revolution of biased signalling of GPCRs comes the possibility of designing drugs that selectively activate therapeutically important pathways over those that lead to undesired side effects. However, determination of ligand bias remains a major bottleneck requiring extensive experimental datasets and in vivo validation which does not always align with in vitro evidence (Kenakin, 2019). 10. Drug repurposing: AI algorithms can screen existing drugs and repurpose them for GPCR-related diseases. By analyzing drug-target interactions and disease pathways, AI can identify potential candidates that may have therapeutic effects on GPCRs. Pros and cons of current technology AI has the potential to revolutionize drug discovery by accelerating the process, optimizing drug design, and improving success rates. However, there are also certain cons associated with the use of AI in this field: 1) the quality and availability of data can be a challenge in AI-driven drug discovery; 2) the need for pattern recognition, often presented in the form of assumptions or hypotheses places similarity-based scoring functions at the core of any AI approach (Sanavia, Birolo, Montanucci, Turina, Capriotti & Fariselli, 2020) with intrinsic limitations (e.g. using sequence information alone to determine similarity cannot adequately predict protein structure (Jumper et al., 2021) ); 3) the same limitation holds when searching for novel receptor ligands, as “ligand-based approaches often bias molecule generation towards previously established chemical space, limiting their ability to identify truly novel chemotypes”(Thomas, Smith, O’Boyle, de Graaf & Bender, 2021) and 4) limit of input data can lead to a phenomenon called “the burden of sequence identity” (Sanavia, Birolo, Montanucci, Turina, Capriotti & Fariselli, 2020). The future According to the authors, the future of AI relies in 6 main areas: 1. Open-source data: accessibility of databases to a wider audience will encourage the development of new ideas and methods. 2. Greater application of unsupervised machine learning: most applications of ML in GPCR drug discovery have relied on traditional, hand-crafted feature construction, which limits the recognition of unknown patterns. Unsupervised deep learning that takes advantage of large unlabelled data (e.g., millions of compounds and assays on CHEMBL) to understand new proteins, ligands and their relationships is the future. 3. Interpretable machine learning: some AI models, such as deep learning neural networks, are often referred to as "black boxes" because they lack transparency and interpretability. Efforts will likely be made to develop AI models that can provide transparent explanations for their predictions and decisions. 4. Towards a comprehensive understanding of GPCRs, ligands, diseases, and their associations: open-access databases from experimental labs and new AI techniques will allow more associations and will promote multi-task learning. 5. Precision medicines for GPCRs: AI can facilitate the development of personalized treatments by analyzing patient data, including genomic information, clinical records, and treatment outcomes. By integrating this data with GPCR-related knowledge, AI can help identify patient-specific GPCR targets and optimize drug selection and dosing. 6. Automated tools for researchers: AI solutions which bring together theoretical, computational, and experimental labs will allow faster discovery and invention. While AI holds great potential, it is important to note that it is not a replacement for experimental validation and human expertise. Instead, it complements and assists researchers in the GPCR drug discovery process. Regulatory challenges, ethical considerations, and the need for interpretability of AI-driven models will need to be addressed to fully realize the potential of AI in GPCR drug discovery. The sharing and collaboration of data across academia, industry, and regulatory bodies will likely increase in the coming years and will facilitate the creation of larger and more diverse datasets for AI model training, improving their accuracy and generalizability. Check the original article at https://pubmed.ncbi.nlm.nih.gov/37161878/ #GPCR #DrGPCR #Ecosystem

Good day readers! We've got some GPCR updates to share with you. Take a look 👀! Save the date and join us next week, May 19th, 2023 for the Dr. GPCR Symposium on GPCR Activation and Signaling. If you want to present a poster, please submit your information using this form. Stay informed with the latest Dr. GPCR News by subscribing to our monthly newsletter. Below is your Classified GPCR News at a glance for May 1 to 7, 2023. GPCR Activation and Signaling Constitutive activity of the dopamine (D5 ) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV 3.2 and CaV 3.3 currents. Characterization of serotonin-5-HTR1E signaling pathways and its role in cell survival. Cholesterol Biases the Conformational Landscape of the Chemokine Receptor CCR3: A MAS SSNMR-Filtered Molecular Dynamics Study. Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2 G protein-coupled receptor. GPCR Binders, Drugs, and more Adenylyl cyclase 6 plays a minor role in the mouse inner ear and retina. GPCRs in Neuroscience GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. GPCRs in Oncology and Immunology Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux. Methods & Updates in GPCR Research Multiplexed selectivity screening of anti-GPCR antibodies. Structural and Molecular Insights into GPCR Function Structural insight into an anti-BRIL Fab as a G-protein-coupled receptor crystallization chaperone. Molecular architecture of the Gαi-bound TRPC5 ion channel. Industry News Addex Therapeutics to Release Q1 2023 Financial Results and Host Conference Call on May 11, 2023 Neurocrine Biosciences Reports First Quarter 2023 Financial Results Find Therapeutics welcomes Dr. Jack Antel to its clinical advisory board Crinetics Pharmaceuticals First Quarter 2023 Earnings: Revenues Beat Expectations, EPS Lags “As Precision Medicine is critical, we cannot think about one size fits all” Dr Pina Cardarelli, Chief Scientific Officer, GPCR Therapeutics Trevena to Participate in Three Upcoming Conferences GPCR Events, Meetings, and Webinars ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) PEGS Boston (May 15 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs Vice President, Medical Affairs Associate Scientist - Technology Senior Research Scientist/Principal Scientist- Technology Tissue Culture Scientist/Tissue Culture Manager Postdoctoral Researcher Director - Targeted Oncology Senior Scientist - Antibody Engineering Scientist—Immuno-Oncology Convergent Research - Senior Scientist, Cell-Based Assay Development Explore Dr. GPCR Ecosystem

Greetings fellow GPCR enthusiasts! This week's GPCR papers feature publications from Drs. Thomas P. Sakmar, Debbie L. Hay, Lukas Grätz, and more. Check out some of the latest GPCR discoveries below! Before you do so, mark your calendars and join us for the Dr. GPCR Symposium on GPCR Activation and Signaling on May 19th, 2023. If you're presenting a poster, submit your poster using the poster form. Also, keep yourself updated with the latest Dr. GPCR News by subscribing to our monthly newsletter. Below is your Classified GPCR News at a glance for April 24 to 30, 2023. Adhesion GPCRs Antiparallel dimer structure of CELSR cadherin in solution revealed by high-speed-atomic force microscopy. Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling. GPCR Activation and Signaling The ancestral ESCRT protein TOM1L2 selects ubiquitinated cargoes for retrieval from cilia. A visual opsin from jellyfish enables precise temporal control of G protein signalling. GPCR Binders, Drugs, and more Allosteric modulation of a human odorant receptor. Direct Selection of DNA-Encoded Libraries for Biased Agonists of GPCRs on Live Cells. Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors. Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells. GPCRs in Cardiology, Endocrinology, and Taste Targeting G Protein-Coupled Receptors for Heart Failure Treatment. Single-cell transcriptome analysis of NEUROG3+ cells during pancreatic endocrine differentiation with small molecules. Novel roles for G protein-coupled receptor kinases in cardiac injury and repair. GPCRs in Neuroscience Evidence that RXFP4 is located in enterochromaffin cells and can regulate production and release of serotonin. GPCRs in Oncology and Immunology Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/11-mediated TGFβ2 activation. Single cell G-protein coupled receptor profiling of Transcription factor 21 expressing activated kidney fibroblasts. Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer. Methods & Updates in GPCR Research NanoBiT- and NanoBiT/BRET-based assays allow the analysis of binding kinetics of WNT-3A to endogenous Frizzled 7 in a colorectal cancer model. Reviews, GPCRs, and more G protein-coupled receptor-targeting antibody-drug conjugates: Current status and future directions. Genetic variants of G-protein coupled receptors associated with pubertal disorders. RGS proteins and their roles in cancer: friend or foe?. Structural and Molecular Insights into GPCR Function Cryo-EM structure of the endothelin-1-ETB-Gi complex. WNT stimulation induces dynamic conformational changes in the Frizzled-Dishevelled interaction. Industry News Orion Biotechnology will be participating in a panel discussion at the LSX World Congress Novel living yeast-based dual biosensor for detecting peptide variants The Galien Foundation Announces 2023 Prix Galien UK Award Candidates Exscientia Appoints Harvard Professor Franziska Michor, Ph.D. to Board of Directors GPCR Events, Meetings, and Webinars ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) NEW PEGS Boston (May 15 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs NEW Associate Scientist - Technology NEW Senior Research Scientist/Principal Scientist- Technology NEW Tissue Culture Scientist/Tissue Culture Manager Postdoctoral Researcher Director - Targeted Oncology Senior Scientist - Antibody Engineering Scientist—Immuno-Oncology Convergent Research - Senior Scientist, Cell-Based Assay Development Explore Dr. GPCR Ecosystem

Hi friends!👋 Take a look at the latest and greatest in GPCR research. This week's GPCR papers feature authors such as Drs. Bryan Roth, Sudarshan Rajagopal, and Graeme Milligan. Save the date! Dr. GPCR Symposium on GPCR Activation and Signaling, May 19th, 2023. Submit your interest in giving a talk or presenting a poster to Hello@DrGPCR.com. Don't miss out! Just 3 weeks away! Stay updated with the latest Dr. GPCR News by subscribing to our monthly newsletter. Below is your Classified GPCR News at a glance for April 17 to 23, 2023. GPCR Activation and Signaling How can we improve the measurement of receptor signaling bias? Phosphorylation barcodes direct biased chemokine signaling at CXCR3. The relaxin receptor RXFP1 signals through a mechanism of autoinhibition. Subcellular location defines GPCR signal transduction. Regulation of the pro-inflammatory G protein-coupled receptor GPR84. GPCR Binders, Drugs, and more Development of a 5-HT7 receptor antibody for the rat: the good, the bad, and the ugly. GPCRs in Cardiology, Endocrinology, and Taste FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome. GPCRs in Neuroscience G protein coupled receptors as targets for transformative neuropsychiatric therapeutics. GPCRs in Oncology and Immunology CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases. Methods & Updates in GPCR Research Solvent accessibility of a GPCR transmembrane domain probed by in-membrane chemical modification (IMCM). Structural and Molecular Insights into GPCR Function Lysophosphatidic acid, a simple phospholipid with myriad functions. Industry News Data Presented at AACR 2023 Highlights Exscientia’s Clinical and Preclinical Development The pathway of opioid drugs into cellular structures Inversago Pharma will present at BBHIC 2023 Orion Biotechnology attended the Swiss Biotech Day Addex Therapeutics attended the Swiss Biotech Day Sosei Heptares presented novel Computational Chemistry and Cheminformatics approaches for GPCR SBDD at UK QSAR Spring Meeting 2023 What the HEK? GPCR Events, Meetings, and Webinars ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs NEW Postdoctoral Researcher Director - Targeted Oncology Senior Scientist - Antibody Engineering Scientist—Immuno-Oncology Convergent Research - Senior Scientist, Cell-Based Assay Development Post Doctoral Fellow Research associate in protein production Vice President, Oncology Clinical Research Explore Dr. GPCR Ecosystem

Transporting Protein-coupled receptors (GPCRs) to the synapse, where they are involved in neurotransmission, is a complex process involving several steps. From a general overview, after GPCRs synthesis in the endoplasmic reticulum, GPCRs are transported to the Golgi apparatus to undergo additional post-translational modifications and sorted for transport to their final destination. Several molecules from the SNARE complex, including vesicle-associated membrane protein 2 (VAMP2), regulate this last step toward the cell membrane [5,7]. VAMP2, also known as synaptobrevin, is a type of SNARE protein found on the synaptic vesicle membrane in neurons and is responsible for binding to the t-SNARE complex, a group of proteins found on the target membrane of the synapse. The t-SNARE complex is composed of two different proteins: syntaxin and SNAP-25; syntaxin is found on the target membrane of the synapse, while SNAP-25 is present on the membrane of the presynaptic neuron. The t-SNARE complex and VAMP2 interact to form the SNARE complex, which is essential for the fusion of the synaptic vesicle membrane with the target membrane, resulting in the release of neurotransmitters into the synapse. However, although the function of the SNARE protein complex in neurotransmitter release has been well characterized, the mechanisms that modulate the delivery of GPCRs to the membrane cell still need to be well known [3-5]. In the context of GPCR recycling, this process is complex and highly regulated that involves multiple molecular players, including SNARE proteins; here, SNARE proteins play a role in the fusion of recycling endosomes with the plasma membrane. Some studies have suggested that VAMP2 may be involved in regulating dopamine D2 receptor signaling by controlling the trafficking of the receptor to the cell surface. In addition, VAMP2 can interact with other GPCRs, such as the beta-2 adrenergic receptor and the mu-opioid receptor (MOR) [1,6,7]. However, the selectivity of SNARE complex proteins to regulate the release of different types of GPCRs during recycling is one of the questions still under investigation in the field. Through developing a high-resolution method, Hao Chen et al. directly visualized the fusion of vesicles containing GPCRs to the plasma membrane. With this technology, they evidenced the presence of VAMP2, specifically in recycling vesicles containing MOR but not B2AR or TFR in HEK293 cells and primary neurons. This study supports the idea that proteins from the fusion machinery are specific about the cargo molecules within the vesicles. These data are fascinating because in the case of MOR, which is a receptor with several splicing variants, its traffic to the membrane can be modified depending on the integrity of its bi-leucine sequence (which is considered a key element in its recycling), which can interact with different fusion proteins and also this different molecular codes will be modulated by different opioids, either endogenous or exogenous, promoving a differential organization of MOR receptors in vesicles with different proteins of the fusion machinery [6]. Since MOR receptor regulates pain perception and reward, the dysfunction in the MOR-SNARE complex interaction can lead to various neurological disorders, such as chronic pain and addiction. Therefore, their comprehension is essential for developing new treatments for these disorders and advancing our understanding of the brain and nervous system. You can consult the article at the following link: https://www.ecosystem.drgpcr.com/structural-and-molecular-insights-into-gpcr-function/vesicle-associated-membrane-protein-2-is-a-cargo-selective-v-snare-for-a-subset-of-gpcrs #GPCR #DrGPCR#Ecosystem Crilly, S.E., W. Ko, Z.Y. Weinberg, and M.A. Puthenveedu. 2021. Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist. Elife. 10:e67478. Drake, M.T., S.K. Shenoy, and R.J. Lefkowitz. 2006. Trafficking of G protein coupled receptors. Circ. Res. 99:570–582. Jurado, S., D. Goswami, Y. Zhang, A.J.M. Molina, T.C. Südhof, and R.C. Malenka. 2013. LTP requires a unique postsynaptic SNARE fusion machinery. Neuron. 77:542–558. Schoch, S., F. Deak, A. K ´ onigstorfer, M. Mozhayeva, Y. Sara, T.C. Südhof, and ¨ E.T. Kavalali. 2001. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science. 294:1117–1122. 5. Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron. 80:675–690. Wang, F., X. Chen, X. Zhang, and L. Ma. 2008. Phosphorylation state of muopioid receptor determines the alternative recycling of receptor via Rab4 or Rab11 pathway. Mol. Endocrinol. 22:1881–1892. Wickner, W., and R. Schekman. 2008. Membrane fusion. Nat. Struct. Mol. Biol. 15:658–664.

Hey there! Are you ready for some exciting news in the GPCR world? Then check this out 👓! Now you can submit your job opening and offer a position in an exclusive GPCR community around the globe with ease by using this form. Save the date! Join us for the upcoming Dr. GPCR Symposium on GPCR Activation and Signaling on May 19th, 2023. While the program is being finalized, if you're interested in giving a talk or presenting a poster, please email us at Hello@DrGPCR.com. Don't miss out on this exciting opportunity! Subscribe to our monthly newsletter for more Dr. GPCR News. Below is your Classified GPCR News at a glance for April 10 to 16, 2023. Adhesion GPCRs Downstream signaling of the disease associated mutations on GPR56/ADGRG1. GPCR Activation and Signaling Ligand-dependent intracellular trafficking of the G protein-coupled P2Y6 receptor. GPCR Binders, Drugs, and more Discovery of SYD5115, a novel orally active small molecule TSH-R antagonist. GPCRs in Cardiology, Endocrinology, and Taste G-protein coupled receptor 19 (GPR19) knockout mice display sex-dependent metabolic dysfunction. GPCRs in Neuroscience GPR160 is not a receptor of anorexigenic cocaine- and amphetamine-regulated transcript peptide. Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens. Multiple subthreshold GPCR signals combined by the G proteins Gαq and Gαs activate the C. elegans egg-laying muscles. GPCRs in Oncology and Immunology G Protein-coupled Receptor-mediated Membrane Targeting of PLCγ2 is Essential for Neutrophil Chemotaxis. Methods & Updates in GPCR Research Activity Map and Transition Pathways of G Protein-Coupled Receptor Revealed by Machine Learning. Computational insights into ligand-induced G protein and β-arrestin signaling of the dopamine D1 receptor. In situ visualization of opioid and cannabinoid drug effects using phosphosite-specific GPCR antibodies. Reviews, GPCRs, and more Internal and external modulation factors of the orexin system (REVIEW). Structural and Molecular Insights into GPCR Function Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor. Transmembrane protein CD69 acts as an S1PR1 agonist. Industry News A Current View of Allosteric GPCR Drug Discovery from the 2nd Annual GPCRs-Targeted Drug Discovery Summit, Boston MA Pathios Therapeutics Unveils PTT-4256, a Highly Potent and Selective Inhibitor of GPR65, in Presentation at American Association for Cancer Research (AACR) Annual Meeting 2023 Setting GPCRs free Dr. Michel Bouvier received the title of Doctor Honoris Causa from the Université de Montpellier Domain Therapeutics presented 3 posters at AACR 2023 Exscientia presented a poster at AACR 2023 Pathios Therapeutics presented a poster at AACR 2023 GPCR Events, Meetings, and Webinars NEW FREE 7th ERNEST GPCR zoominar (April 20, 2023) SLAS 2023 Building Biology in 3D Symposium. (April 20 - 21, 2023) Swiss Biotech Day (April 24 - 25, 2023) ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs NEW Director - Targeted Oncology NEW Senior Scientist - Antibody Engineering NEW Scientist—Immuno-Oncology Convergent Research - Senior Scientist, Cell-Based Assay Development Post Doctoral Fellow Research associate in protein production Vice President, Oncology Clinical Research PostDoctoral Associate PostDoctoral Position Team Lead protein production and profiling Explore Dr. GPCR Ecosystem

Hello, fellow GPCR enthusiasts! 👋 Check out the latest advancements in GPCR studies. For Dr. GPCR News, please subscribe to our monthly newsletter. Also, please mark your calendar for the next Dr. GPCR Symposium on GPCR Activation and Signaling held on May 19th, 2023. The program is under construction but if you’d like to give a talk or present a poster, email us at Hello@DrGPCR.com Below is your Classified GPCR News at a glance for April 3rd to 9th, 2023. GPCR Activation and Signaling Phosphorylation barcodes direct biased chemokine signaling at CXCR3. SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression. GABABR silencing of nerve terminals. GPCR Binders, Drugs, and more Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands. The molecular basis of the antidepressant action of the magic mushroom extract, psilocin. Sodium is a negative allosteric regulator of the ghrelin receptor. GPCRs in Cardiology, Endocrinology, and Taste Novel roles for G protein-coupled receptor kinases in cardiac injury and repair. DRD1 is exempt from TGFβ-mediated antifibrotic GPCR landscape tampering in lung fibroblasts. βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids. GPCRs in Neuroscience G protein-coupled receptors (GPCRs) as Potential Therapeutics for Psychiatric Disorders. Local 5-HT signaling bi-directionally regulates the coincidence time window for associative learning. GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency. GPR37L1 controls maturation and organization of cortical astrocytes during development. Methods & Updates in GPCR Research The Road to Quantitative Lipid Biochemistry in Living Cells. Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor. Reviews, GPCRs, and more Heterotrimeric G proteins regulate planarian regeneration and behavior. Transcriptomic profiling of sex-specific olfactory neurons reveals subset-specific receptor expression in Caenorhabditis elegans. β- Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives. Structural and Molecular Insights into GPCR Function Sub-millisecond conformational dynamics of the A2A adenosine receptor revealed by single-molecule FRET. Vesicle-associated membrane protein 2 is a cargo-selective v-SNARE for a subset of GPCRs. Industry News Orion Biotechnology at the AACR 2023. Eurofins Discovery Acquires CALIXAR, Expanding Integrated Drug Discovery Capabilities and Expertise. Domain Therapeutics to present three posters at AACR 2023 annual meeting. GPCR Events, Meetings, and Webinars NEW AACR 2023 - American Association for Cancer Research (April 14 - 19, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 21, 2023) Swiss Biotech Day (April 24 - 25, 2023) NEW ASPET 2023 - American Society for Pharmacology and Experimental Therapeutics (May 18 - 21, 2023). SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs Convergent Research - Senior Scientist, Cell-Based Assay Development Post Doctoral Fellow Research associate in protein production Vice President, Oncology Clinical Research PostDoctoral Associate PostDoctoral Position Team Lead protein production and profiling Pharmacologist Postdoctoral positions at UC San Diego Medical Director CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Explore Dr. GPCR Ecosystem

Canonical chemokine receptors – scavenging “decoys” Chemokine receptors coordinate cell migration upon interaction with their cognate chemokines. Upon activation, chemokine receptors coupe to the Gαi class of heterotrimeric G proteins, which, in turn, activate signaling pathways that ultimately lead to cell migration. The chemokine receptor family comprises 19 canonical chemokine receptors together with 4 atypical chemokine receptors (ACKRs) which do not couple to G proteins and 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 chemokine receptors that bind to the same ligand(s) (R. J. B. Nibbs et al. 2013). Although less characterized, canonical chemokine receptor systems have been also shown to not only directly regulatE migration but also play a scavenging role (e.g. CCR2, CXCR2, CXCR3, and CX3CR1) (A. E. Cardona et al. 2008). CCR2 is an example of a dual-function receptor that directly regulates both cell migration and scavenging (S. Volpe et al. 2012). Molecular signature of CCR2 scavenging - no G proteins, no GRKs, no arrestins, and no clathrin Chemokine scavenging mechanism involves internalization and recycling of the receptor with clearance of the ligand from the extracellular space however, the molecular cues involved in this process are poorly characterized. In this study, the molecular signature of CCR2 scavenging role is investigated. CCR2 canonical signaling requires the activation of Gαiβγ, followed by phosphorylation of the receptor C terminus by G protein receptor kinases (GRKs), specifically GRK2 and GRK3 (A. M. Aragay et al. 1998). Then β-Arrestin recruitment takes place allowing receptor internalization through clathrin-mediated pits (V. V. Gurevich, et al. 2018; Y. A. Berchiche et al. 2011). In this study, the role of these 3 molecular players (G proteins, GRKs, and β-arrestin) is investigated. Removal of G proteins by using CRISPR KO of Gαi (Gαi KO) or KO of all Gα subtypes (Gα_all KO) (M. Grundmann et al. 2018), did not affect chemokine scavenging, consistent with prior work (S. Volpe et al. 2012; B. N. Zhao et al. 2019). Recruitment of both β-arrestin1 and β-arrestin2 was significantly diminished iin Gαi KO and Gα_all KO HEK293 cells, however there was only a minor loss in receptor internalization, which is surprising since internalization is known to be a consequence of β-arrestin recruitment. In addition, constitutive internalization of CCR2 was shown to be G protein-independent by a “prelabel” flow cytometry assay (B. N. Zhao et al. 2019) together with confocal fluorescence microscopy. Regarding GRKs role in CCR2 scavenging, BRET, flow cytometry and fluorescence microscopy readouts revealed that CCL2-dependent internalization was partially decreased in GRK2/3 KO cells and almost completely lost in the GRK2/3/5/6 KO cells, whereas constitutive receptor internalization was unaffected. Moreover, HEK293 cells with CRISPR KO of both β-arrestin1 and β-arrestin2 only led to a small but measurable loss of CCL2 scavenging and did not affect constitutive receptor internalization, with the same observations made for CCR2-expressing THP-1 monocytic cell line, together with an increase in migration, consistent with the role of β-arrestin in receptor desensitization. Although some GPCRs constitutively internalize through clathrin-coated pits independently of phosphorylation and β-arrestin (M. M. Paing et al. 2022; J. L. Parent, et al. 2001), inhibition of clathrin-mediated endocytosis (CME) did not affect the ability of CCR2 to scavenge chemokine and had only a small effect on constitutive internalization. Using fast recycling, slow recycling, and late endosomal recycling markers, CCR2 was also shown to be rapidly sorted into fast-recycling Rab4-positive endosomes in a more sustained manner compared to the atypical scavenging receptor ACKR3, and Rab7-positive late endosomes. CCR2 was also shown to be resistant to degradation and most likely recycling through the trans-Golgi network (TGN) where Rab7 is associated (A. Sapmaz et al. 2019, M. N. J. Seaman 2012). The ability to rapidly recycle, which was shown by a chemokine washout BRET assay (Y. Namkung et al. 2016), and avoid depletion may also contribute to its ability to efficiently scavenge chemokine. CCR2 vs CCR1 scavenging signatures CCR1 is constitutively phosphorylated, constitutively interacts with β-arrestin2, and constitutively internalizes in a β-arrestin2–dependent manner (C. T. Gilliland et. al 2013). In line, β-Arrestin KO cells showed a major reduction in CCL14 scavenging by CCR1, in contrast with a minor effect observed for CCR2. β-arrestin KO cells revealed the rapid reassociation of Gαi and Gβγ on CCR1, in contrast with CCR2, indicating that β-arrestin regulates scavenging and signaling of CCR1 to a greater extent than CCR2. Functional relevance and implications of scavenging of canonical chemokine receptors Clearing circulating chemokines and chemokines from tissue microenvironments has been well described for ACKRs which work in a team with canonical chemokine receptor to drive regulated immunological responses and inflammatory conditions, preventing overstimulation and activation. However, this scavenging role has been also described for several canonical chemokine receptors, including CCR2. In this study, it is revealed that CCR2 scavenging role was largely independent of the classical GPCR signaling pathways, revealing the existence of two distinct functional populations – one that directs cell migration and one that regulates scavenging. But why do canonical chemokine receptors have this dual role in physiology? Scavenging may allow cells to continuously migrate by remaining responsive to chemokines (S. Volpe et al. 2012); it dampens the inflammatory response when needed (C. A. H. Hansell et al. 2011); and it may interfere with other chemokine receptors which share the ligands and affect cell migration (A. E. Cardona et al. 2008). However, it is important to note that this scavenging role does not occur in all chemokine receptor systems such as CXCR4, which relies on ACKRs. How balanced is this dual role? In monocytes and dendritic cells exposed to treatments mimicking inflammation, CCR1, CCR2, and CCR5 switch purely to scavenging (G. D’Amico 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 not yet described to play a role. What are the implications in drug discovery? This scavenging function should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand binding. CCR2 inhibition leads to inhibition of scavenging and elevated plasma levels of CCL2 (Y. Wang et al. 2009; R. J. Aiello et. al 2010) which may ultimately compete with receptor antagonists, thereby decreasing the efficacy (J. Gilbert et. al 2011). This study provides a comprehensive analysis of CCR2 scavenging role however to fully understand the role of canonical chemokine receptors scavenging population pathophysiology, a better understanding of the regulatory mechanisms will be required. Check the original article at https://pubmed.ncbi.nlm.nih.gov/36719944/ #GPCR #DrGPCR#Ecosystem

Hello Readers👋, This week in the GPCR news we have collected the most up-to-date news for you. Enjoy! For more great content, subscribe to our Dr. GPCR News monthly newsletter. Also, please mark your calendar for the next Dr. GPCR Symposium on GPCR Activation and Signaling held on May 19th, 2023. The program is under construction but if you’d like to give a talk or present a poster, email us at Hello@DrGPCR.com Below is your Classified GPCR News at a glance for March 27th to April 4th, 2023. Adhesion GPCRs Optimized genetic code expansion technology for time-dependent induction of adhesion GPCR-ligand engagement. The adhesion G-protein-coupled receptor VLGR1/ADGRV1 controls autophagy. GPCR Activation and Signaling Butyrate potentiates Enterococcus faecalis lipoteichoic acid-induced inflammasome activation via histone deacetylase inhibition. Negative allosteric modulation of the glucagon receptor by RAMP2. Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins (RAMPs). Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia. Cannabinoid Tolerance in S426A/S430A x β-Arrestin 2 Knockout Double-Mutant Mice. Gαi-derived peptide binds the µ-opioid receptor. Deficiency of G protein-coupled receptor Gpr111/Adgrf2 causes enamel hypomineralization in mice by alteration of the expression of kallikrein-related peptidase 4 (Klk4) during pH cycling process. GPCR Binders, Drugs, and more Predicting allosteric sites using fast conformational sampling as guided by coarse-grained normal modes. Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. GPCRs in Cardiology, Endocrinology, and Taste Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a Gi Protein/ROCK/PKD-Sensitive Manner. Dietary compounds activate an insect gustatory receptor on enteroendocrine cells to elicit myosuppressin secretion. GPCRs in Neuroscience Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory. Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor. GPCRs in Oncology and Immunology Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure. Methods & Updates in GPCR Research Discovery and design of G protein-coupled receptor targeting antibodies. A Vaccinia-based system for directed evolution of GPCRs in mammalian cells. First complete genome sequence of lumpy skin disease virus directly from a clinical sample in South India. Reviews, GPCRs, and more NMR applications to GPCR recognition by peptide ligands. Developmental and homeostatic signaling transmitted by the G-protein coupled receptor FPR2. Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension. Therapeutic potential of opioid receptor heteromers in chronic pain and associated comorbidities. Investigating the potential of GalR2 as a drug target for neuropathic pain. The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors. Structural and Molecular Insights into GPCR Function Predicted Three-Dimensional Structure of the GCR1 Putative GPCR in Arabidopsis thaliana and Its Binding to Abscisic Acid and Gibberellin A1. Structural insights into constitutive activity of 5-HT6 receptor. Industry News Confo Therapeutics Enters into Collaboration Agreement with Daiichi Sankyo to Discover Novel Medicines for CNS Diseases Addex Reports Full Year 2022 Financial Results and Provides Corporate Update Sosei Heptares Announces the Publication of its Inaugural ESG Report, for the Financial Year ended 31 December 2022 Addex Raises $5.0 Million in Equity Financing Testing the limits of SMILES-based de novo molecular generation with curriculum and deep reinforcement learning Structure Therapeutics Reports Fourth Quarter and Full Year 2022 Financial Results and Recent Highlights Salipro Biotech publishes research in Scientific Reports on structure-function studies for membrane proteins in collaboration with AstraZeneca Expansion of precision oncology pipeline announced by Exscientia Upcoming start-up ecosystem - leadXpro and InterAx part of Fujitsu CaaS GPCR Events, Meetings, and Webinars SLAS 2023 Building Biology in 3D Symposium. (April 20 - 21, 2023) Swiss Biotech Day (April 24 - 25, 2023) SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). FREE Symposium - IPI Surfacing (June 15, 2023) Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) FREE 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signalling (June 30 - July 1, 2023) 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). 3rd Annual Meeting IRN I-GPCRNet (October 25 - 27, 2023) GPCR Jobs NEW Convergent Research - Senior Scientist, Cell-Based Assay Development NEW Post Doctoral Fellow NEW Research associate in protein production NEW Vice President, Oncology Clinical Research NEW PostDoctoral Associate NEW PostDoctoral Position Team Lead protein production and profiling Pharmacologist Postdoctoral positions at UC San Diego Medical Director CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Explore Dr. GPCR Ecosystem