Hello Readers👋, We're excited to have you in the Dr. GPCR Ecosystem. Every week, we send you the most relevant news, research, and advancements in the field. For Dr. GPCR News, subscribe to our monthly newsletter. This month on the Dr. GPCR News video edition, we chatted with Dr. Oliver Hartley. Below is your Classified GPCR News at a glance for March 20th to 26th, 2023. GPCR Activation and Signaling Targeting biased signaling by PAR1: Function and molecular mechanism of parmodulins. The Wnt pathway protein Dvl1 targets Somatostatin receptor 2 for lysosome-dependent degradation. Loss of biased signaling at a G protein-coupled receptor in overexpressed systems. GPCR Binders, Drugs, and more A snake toxin as a theranostic agent for the type 2 vasopressin receptor Small-Molecule Fluorescent Ligands for the CXCR4 Chemokine Receptor. GPCRs in Cardiology, Endocrinology, and Taste Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease GPCRs in Oncology and Immunology Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion. CCL5-producing migratory dendritic cells guide CCR5+ monocytes into the draining lymph nodes. Methods & Updates in GPCR Research The application of targeted protein degradation technologies to G protein-coupled receptors. Structural and Molecular Insights into GPCR Function Physiological changes in bilayer thickness induced by cholesterol control GPCR rhodopsin function. Evidence that RXFP4 is located in enterochromaffin cells and can regulate production and release of serotonin. Ultrafast structural changes direct the first molecular events of vision. New insights into GPCR coupling and dimerisation from cryo-EM structures. Industry News Domain Therapeutics was one of the 4 Biotech Trophy nominees at 2023 HealthTech awards. The delisting dilemma: Why do so many biotechs face being kicked off the Nasdaq?. Exscientia Business and Financial Update for the Full Year 2022. Sosei Heptares Confirms Changes to its Board and Executive Management Team at Annual Shareholders’ Meeting. Function Therapeutics has been awarded a Phase 1 SBIR grant from NSF. Function Therapeutics has a new website. Call for GPCR Papers GPCRs: Signal Transduction. Ends tomorrow - March 31st, 2023. GPCR Events, Meetings, and Webinars FREE 5th ERNEST GPCR ECI zoominar. (March 30, 2023) NEW Webinar - Antiverse: Engineering the Future of Drug Discovery (March 30, 2023) NEW Molecular Dynamics in Pharma (March 31, 2023) NEW FREE Workshop - Challenges in GPCR Drug Discovery (March 31, 2023) 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). NEW 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 Team Lead protein production and profiling NEW Pharmacologist Postdoctoral positions at UC San Diego Medical Director CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Scientist Corporate Strategy Analyst PhD candidate or Postdoc. Director, Head of PMO. Associate Scientist, Protein Science. Explore Dr. GPCR Ecosystem

Hello Readers👋, Welcome to our GPCR weekly newsletter! We thrive to keep you up-to-date with everything happening in the world of GPCR. Remember, you can always adjust your email preferences in your account settings. For Dr. GPCR News, please subscribe to our monthly newsletter. The first Dr. GPCR Symposium starts tomorrow! If you'd like to present a poster, please submit yours today. There is still time. There is no limit to the number of posters we can accommodate, so hurry and submit your poster so that we can add it to the list of posters and increase the number of people who can ''stop by'' it tomorrow. Below is your Classified GPCR News at a glance for March 13th to 19th, 2023. Adhesion GPCRs Crystal Structure of the Extracellular Domains of GPR110. Monitoring paxillin in astrocytes reveals the significance of the adhesion GPCR VLGR1/ADGRV1 for focal adhesion assembly. GPCR Activation and Signaling Components of TOR and MAP kinase signaling control chemotropism and pathogenicity in the fungal pathogen Verticillium dahliae. A Rab10-ACAP1-Arf6 GTPases cascade modulates M4 muscarinic acetylcholine receptor trafficking and signaling. Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation. The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response. GPCR Binders, Drugs, and more Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor. Pharmacological characterization of novel small molecule agonists and antagonists for the orphan receptor GPR139. A small molecule ligand for the novel pain target, GPR171, produces minimal reward in mice. Monitoring the Reversibility of GPCR Signaling by Combining Photochromic Ligands with Label-free Impedance Analysis. GPCRs in Cardiology, Endocrinology, and Taste Structure-based design of novel melanin-concentrating hormone receptor-1 ligands based on saturated nitrogen-containing heterocycles. GPCRs in Neuroscience Physiological Condition-Dependent Changes in Ciliary GPCR Localization in the Brain. Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members. GPCRs in Oncology and Immunology Expanding role of CXCR2 and therapeutic potential of CXCR2 antagonists in inflammatory diseases and cancers. Reviews, GPCRs, and more The leukotriene B4 receptors BLT1 and BLT2 as potential therapeutic targets. New paradigms in purinergic receptor ligand discovery. G protein-coupled receptor pharmacology - insights from mass spectrometry. Structural and Molecular Insights into GPCR Function Structural basis of selective cannabinoid CB2 receptor activation. Structural basis for motilin and erythromycin recognition by motilin receptor. Industry News Addex Announces Upcoming Conferences It Will Participate For H1 2023 Learn more about Exscientia new pipeline candidate, EXS74539 Domain Therapeutics unveiled its 2023 women-men professional equality index Octant introduces Hypatia, their New Robotic Drug Hunter GPCR Therapeutics Announces Publication in Nature Scientific Reports on Novel Anticancer Therapy An extraordinary opportunity to generate proprietary chemo-informatics for GPCR drug discovery - Design Pharmaceuticals Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars NEW 4th ERNEST GPCR ECI zoominar. (March 23, 2023) NEW 5th ERNEST GPCR ECI zoominar. (March 30, 2023) SLAS 2023 Building Biology in 3D Symposium. (April 20 - 21, 2023) NEW 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). NEW Training School on “Cell-based assays to study Adhesion GPCR function". (June 28 - 30, 2023) 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 Postdoctoral positions at UC San Diego Medical Director CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Scientist Corporate Strategy Analyst PhD candidate or Postdoc. Director, Head of PMO. Associate Scientist, Protein Science. Explore Dr. GPCR Ecosystem

Hello Readers👋, Thank you for being here with us this week. We work tirelessly to bring you informative and exciting news about the world of GPCR every Thursday. To get the latest, Dr. GPCR News, don't forget to sign up for our monthly newsletter. Are you ready for our first Dr. GPCR Symposium event held on March 24th? If you'd like to present a poster, please submit yours today. There is no limit to the number of posters we can accommodate, so hurry and submit your poster so that we can add it to the list of posters and increase the number of people who can ''stop by'' it on March 24th, 2023. Below is your Classified GPCR News at a glance for March 6th to 12th, 2023. GPCR Activation and Signaling Autoregulation of GPCR signalling through the third intracellular loop. GPCR Binders, Drugs, and more Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium. Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2. Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation. GPCRs in Neuroscience Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers. The crosstalk between 5-HT2AR and mGluR2 in schizophrenia. GPCRs in Oncology and Immunology GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer. Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery. Structural and Molecular Insights into GPCR Function Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members. Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation. Structural basis of peptide recognition and activation of endothelin receptors. Industry News Professor Dame Carol Robinson Received 2023 ASMS John.B.Fenn Award Exscientia Announces Expansion of its Precision Oncology Pipeline Exscientia to Present Data Highlighting Pipeline and Precision Medicine Platform at AACR Fast Company has named Exscientia as one of the Most Innovative Companies of 2023 Dirk Loeffert CEO & Founder DesignPharma Interview GPCR-targeting drugs: A renewed focus on a ubiquitous group of proteins arcoscreen will be at Bio-Europe 2023 in Basel. Domain Therapeutics was nominated for the Trophée de l'Innovation Technologique (Technological Innovation Award) Sosei Heptares Receives Approval for Change of Market Listing Segment to the Tokyo Stock Exchange Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 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). 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 CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Scientist Corporate Strategy Analyst PhD candidate or Postdoc. Director, Head of PMO. Associate Scientist, Protein Science. PhD Studentship - Integrated Approaches In Pharmacology, Computer Simulations And Machine Learning To Predict Ligand Signaling Pathways Via The Anti-Inflammatory Receptor Gpr84. PhD Studentship - Insight Into The Neuroprotective Function Of The Prostaglandin Receptor Ep2. Explore Dr. GPCR Ecosystem

Hello Readers👋, GPCR weekly newsletter is here! Prepare to stay informed of the most recent findings, developments, and news in the industry. Keep in mind that you can always change your email preferences in your account settings. Join us in our monthly newsletter to receive Dr. GPCR News. Great News! We are excited to welcome you to the first Dr. GPCR Symposium event held on March 24th. If you'd like to present a poster, please submit yours today. There is no limit to the number of posters we can accommodate, so hurry and submit your poster so that we can add it to the list of posters and increase the number of people who can ''stop by'' it on March 24th, 2023. Below is your Classified GPCR News at a glance for February 27th to March 5th, 2023. GPCRs in Cardiology, Endocrinology, and Taste Dietary compounds activate an insect gustatory receptor on enteroendocrine cells to elicit myosuppressin secretion. GPCRs in Neuroscience Physiological Condition Dependent Changes in Ciliary GPCR Localization in the Brain. Establishment of a CaCC-based Cell Model and Method for High-throughput Screening of M3 Receptor Drugs. Publisher Correction: Transcriptional adaptation of olfactory sensory neurons to GPCR identity and activity. Elucidation of a dynamic interplay between a beta-2 adrenergic receptor, its agonist, and stimulatory G protein. GPCRs in Oncology and Immunology GPR143 controls ESCRT-dependent exosome biogenesis and promotes cancer metastasis. Methods & Updates in GPCR Research Time- and cost-efficient bacterial expression and purification of potato apyrase. FSHR activation through small molecule modulators: Mechanistic insights from MD simulations. Reviews, GPCRs, and more Short-chain fatty acids: possible regulators of insulin secretion. Function and structure of bradykinin receptor 2 for drug discovery. Developing novel antifungals: lessons from G protein-coupled receptors. Function and regulation of GPR84 in human neutrophils. Structural and Molecular Insights into GPCR Function The activation mechanism and antibody binding mode for orphan GPR20. Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells. Industry News Design Pharmaceuticals has a new website Confo Therapeutics Announces Global Licensing Agreement with Lilly for Peripheral Pain Candidate, CFTX-1554 Cardiff-based Antiverse raises €2.8M for its computational antibody drug discovery platform Antiverse identifies therapeutic antibodies targeting GPCRs CEO Andrew Hopkins on Exscientias AI-Driven Approach to Modern Drug Discovery Arcoscreen will present in the start-up village at Future Labs Live Basel Exscientia Announces Collaboration with Charité to Advance Development of Precision Medicine Platform Sosei Heptares and Neurocrine Biosciences won Top Out-Licensing Deal on the 8th annual Japan Deal of the Year Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars ERNEST ECI zoominar. (March 9) GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 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). 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 PhD candidate or Postdoc. Director, Head of PMO. Associate Scientist, Protein Science. PhD Studentship - Integrated Approaches In Pharmacology, Computer Simulations And Machine Learning To Predict Ligand Signaling Pathways Via The Anti-Inflammatory Receptor Gpr84. PhD Studentship - Insight Into The Neuroprotective Function Of The Prostaglandin Receptor Ep2. Computational drug design PhD student at the Department of Drug Design and Pharmacology. Computational drug design postdoc at the Department of Drug Design and Pharmacology. Software / database development PhD student at Department of Drug Design and Pharmacology. Software / database development postdoc at the Department of Drug Design and Pharmacology. Explore Dr. GPCR Ecosystem

Hello Readers👋, Thank you for joining us this week. Each week on Thursday, you receive informative and exciting news about GPCRs. And don't forget, for Dr. GPCR news content, make sure to subscribe to our monthly newsletter for Dr. GPCR News. Sometimes we may miss publications. If you'd like to suggest papers to include in our news, please email them to us at Hello@DrGPCR.com. Below is your Classified GPCR News at a glance for February 20th to 26th, 2023. GPCR Activation and Signaling Coupling between GPR143 and dopamine D2 receptor is required for selective potentiation of dopamine D2 receptor function by L-3,4-dihydroxyphenylalanine in the dorsal striatum. All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor. Allosteric modulation of conserved motifs and helices in 5HT2BR: Advances drug discovery and therapeutic approach towards drug resistant epilepsy. Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs. Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling GPCR Binders, Drugs, and more Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss. Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression. Application of computational methods for class A GPCR Ligand discovery. Gαi-derived peptide binds the µ-opioid receptor. GPCRs in Cardiology, Endocrinology, and Taste α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer's Disease. Gβγ subunits co-localize with RNA polymerase II and regulate transcription in cardiac fibroblasts. Slow-rising and fast-falling dopaminergic dynamics jointly adjust negative prediction error in the ventral striatum. Methods & Updates in GPCR Research GPCRLigNet: rapid screening for GPCR active ligands using machine learning. A robust approach for MicroED sample preparation of lipidic cubic phase embedded membrane protein crystals. Reviews, GPCRs, and more Cell-trafficking impairment in disease-associated LPA6 missense mutants and a potential pharmacoperone therapy for autosomal recessive woolly hair/hypotrichosis. Structural and Molecular Insights into GPCR Function Structure-based design of novel melanin-concentrating hormone receptor-1 ligands based on saturated nitrogen-containing heterocycles. Industry News Josephine (Pina) Cardarelli from GPCR Therapeutics on Beyond Biotech Podcast Crinetics Pharmaceuticals Reports Fourth Quarter And Full Year 2022 Financial Results And Provides Corporate Update Alastair Brown from Sosei Heptares, will present at the 18th Annual Biomarkers Congress. A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars 2nd ERNEST Training School. (February 20 - March 3, 2023). WEBINAR Using integrative biophysical approaches to understand GPCR regulation by β-arrestins. (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs PhD Studentship - Integrated Approaches In Pharmacology, Computer Simulations And Machine Learning To Predict Ligand Signaling Pathways Via The Anti-Inflammatory Receptor Gpr84 PhD Studentship - Insight Into The Neuroprotective Function Of The Prostaglandin Receptor Ep2 Computational drug design PhD student at the Department of Drug Design and Pharmacology Computational drug design postdoc at the Department of Drug Design and Pharmacology Software / database development PhD student at Department of Drug Design and Pharmacology Software / database development postdoc at the Department of Drug Design and Pharmacology Postdoc in Bioinformatics/Data Science at Department of Drug Design and Pharmacology Scientist/Senior Scientist (Research Software Engineer) Senior Scientist – Native Mass Spectrometry Speculative Applications (Protein Biochemistry) Speculative Applications (Mass Spectrometry) Speculative Applications (Chemistry) Explore Dr. GPCR Ecosystem

Regulator G protein Signaling (RGS) proteins are critical components of the intracellular signaling pathways that mediate the effects of G protein-coupled receptors (GPCRs). Upon activation, GPCRs have conformational changes that allow the coupling and subsequent activation of the G-protein heterotrimeric complex (α, β, and γ); it is at this point when the RGS proteins play a key role in the deactivation of the alpha subunit contributing to the termination of the G protein-mediated signaling cascades[1, 2]. RGS proteins are a family with around 20 members characterized by the presence of a conserved RGS-homology (RH) domain. This domain contains the catalytic core that catalyzes the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate of the G protein α subunit promoting the switch from activated to an inactivated state[3]. In addition to the RGS domain, RGS proteins also contain a range of other structural motifs that are critical for their function, including the G protein-binding domain, the DEP (Dishevelled, Egl-10 and Pleckstrin domain) domain, and the GoLoco motif[2, 3]. Role of RGS proteins in regulating GPCR signaling: Recent studies have revealed that the interaction between RGS proteins and GPCRs is mediated by a range of structural motifs, including the G protein-binding (GB) and the RGS domains. The interaction between RGS proteins and GPCRs is highly specific and tightly regulated; mutations in the RGS domain and other structural motifs have been shown to alter the specificity and potency of the RGS-GPCR interaction[2]. As negative regulators of GPCR signaling, RGS proteins play a critical role in regulating the duration and amplitude of GPCR signaling. For example, μ opioid receptor (MOR) interacts with Gαi/o and Gαz subunits, which have a slow enzymatic GTPase activity requiring the action of RGSs proteins. RGSs bind to GTP-bound Gα to accelerate GTP hydrolysis reducing the activity of the Gα subunit and resulting in negative regulation of MOR downstream signaling[3, 4]. Besides the differences in their structural complexity, some members of the RGS family are selective for certain GPCRs, as a proof RGS4 which is expressed in the brain, has been shown to modulate dopamine signaling by specifically regulating the activity of the dopamine D2 receptor; enhancing the activity of the G protein that is coupled to the receptor and leading to a decrease in dopamine signaling[4, 5]. Another signaling pathway related to RGS4 involves the regulation of the immune response. RGS4 is expressed in various immune cells, including T cells and B cells, and has been shown to modulate immune cell activation and cytokine production. RGS4 acts as a negative regulator of T cell activation, and its expression is upregulated in response to T cell activation[6]. Implications of RGS protein dysregulation in disease: The Dysregulation of RGS proteins has been implicated in a range of diseases, including cardiovascular disease, pain, hypertension, and cancer. In cardiovascular disease, RGS proteins play a critical role in regulating blood pressure and vascular function. Relating to pain, RGS4 in pain regulation is a topic of increasing interest because it has been identified as a key player in the modulation of nociception[7]. In hypertension, dysregulation of RGS proteins has been shown to contribute to the pathogenesis of the disease. While in cancer, RGS proteins are involved in regulating cell proliferation and survival[8]. In conclusion, RGS proteins are essential modulators for the GPCR signaling mediated by G proteins, which play a crucial role in regulating a range of physiological processes. The dysregulation of these proteins has been implicated in a range of diseases, and understanding the mechanisms of these complex molecules is crucial for developing effective therapies. 1. Tesmer, J.J., et al., Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell, 1997. 89(2): p. 251-61. https://pubmed.ncbi.nlm.nih.gov/9108480/ 2. Senese, N.B., et al., Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management. Front Mol Neurosci, 2020. 13: p. 5. https://pubmed.ncbi.nlm.nih.gov/32038168/ 3. Hollinger, S. and J.R. Hepler, Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev, 2002. 54(3): p. 527-59. https://pubmed.ncbi.nlm.nih.gov/12223533/ 4. Wang, Q., L.Y. Liu-Chen, and J.R. Traynor, Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein in SH-SY5Y cells. J Biol Chem, 2009. 284(27): p. 18357-67. https://pubmed.ncbi.nlm.nih.gov/19416973/ 5. Zhuang, Y., et al., Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell, 2021. 184(4): p. 931-942.e18. https://pubmed.ncbi.nlm.nih.gov/33571431/ 6. Wang, D., The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity. Immunopharmacol Immunotoxicol, 2018. 40(3): p. 187-192. https://pubmed.ncbi.nlm.nih.gov/29433403/ 7. Avrampou, K., et al., RGS4 Maintains Chronic Pain Symptoms in Rodent Models. J Neurosci, 2019. 39(42): p. 8291-8304. https://pubmed.ncbi.nlm.nih.gov/31308097/ 8. Hu, Y., et al., Identification of a five-gene signature of the RGS gene family with prognostic value in ovarian cancer. Genomics, 2021. 113(4): p. 2134-2144. https://pubmed.ncbi.nlm.nih.gov/33845140/

Hello Readers👋, Welcome to our GPCR weekly newsletter! Get ready to stay up-to-date with the latest research, advancements, and news in the field. Remember, you can always adjust your email preferences in your account settings. If you'd like to suggest papers to include in our news, please email them to us at Hello@DrGPCR.com. For Dr. GPCR News, please subscribe to our monthly newsletter. Below is your Classified GPCR News at a glance for February 13th to 19th, 2023. GPCR Activation and Signaling Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. Anionic phospholipids control mechanisms of GPCR-G protein recognition. Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding. From outside to inside and back again: the lysophosphatidic acid-CCN axis in signal transduction. Octopamine and tyramine signalling in Aedes aegypti: Molecular characterization and insight into potential physiological roles. The spatial distribution of GPCR and Gβγ activity across a cell dictates PIP3 dynamics. GPCR Binders, Drugs, and more Novel targets for potential therapeutic use in Diabetes mellitus. Reviews, GPCRs, and more Single nucleotide variations encoding missense mutations in G protein-coupled receptors may contribute to autism. Understanding Neuropeptide Transmission in the Brain by Optical Uncaging and Release. Structural and Molecular Insights into GPCR Function Quantitative analysis of sterol-modulated monomer-dimer equilibrium of the β1-adrenergic receptor by DEER spectroscopy. Industry News Trevena Announces Publication of OLINVYK Respiratory Physiology Study In Anesthesiology Neurocrine Biosciences discovers new muscarinic M4 receptor antagonists Alexander S. Hauser on receiving 4.8 mill DKK from Carlsberg Foundation’s Semper Ardens: Accelerate programme. From the scientist’s view: a conversation with … Chris Tate AI is dreaming up drugs that no one has ever seen. Now we've got to see if they work. Artificial Intelligence for Drug Discovery Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). WEBINAR Using integrative biophysical approaches to understand GPCR regulation by β-arrestins. (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 B Building Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Computational drug design PhD student at the Department of Drug Design and Pharmacology Computational drug design postdoc at the Department of Drug Design and Pharmacology Software / database development PhD student at Department of Drug Design and Pharmacology Software / database development postdoc at the Department of Drug Design and Pharmacology Postdoc in Bioinformatics/Data Science at Department of Drug Design and Pharmacology Scientist/Senior Scientist (Research Software Engineer) Senior Scientist – Native Mass Spectrometry Speculative Applications (Protein Biochemistry) Speculative Applications (Mass Spectrometry) Speculative Applications (Chemistry) Post-Doctoral Research Assistant Research Fellow - School of Physics and Astronomy Postdoctoral Research Associate (Fixed Term) Explore Dr. GPCR Ecosystem

Glycosylation and sulfation – N-terminal PTMs on chemokine receptors The interaction of chemokine receptors with their cognate chemokine ligands is generally described by the two-step/two-site model - the first step characterized by the interaction between the extracellular domains of the receptor and the structural core domain of the chemokine (CRS1); and the second step featured by the interaction between the N-terminus of the chemokine and the extracellular loops and transmembrane domains of the receptor (CRS2), which will trigger conformational changes that ultimately lead to receptor activation (Scholten D et al. 2012, Kufavera I et al. 2017). Within the CRS1 ineraction mode, the N-terminal region of chemokine receptors is indispensable for chemokine binding, where the negatively charged residues, as a consequence of the negatively charged aminoacids and post-translational modifications (PTMs), contribute to the high affinity binding to the positively charged groove on the chemokine. N-terminal PTMs include sulfation and glycosylation which contribute to the overall negative charge of the N-terminus fine-tuning chemokine binding. Chemokine receptors have either reported or predicted sites of N-acetyl galactosamine (GalNAc)-type O-glycosylation in their N-termini as well as sulfation, both PTMs which co-localize in the Trans-Golgi network (Mehta AY et al. 2020). In silico analyses done in this study with the NetOGlyc 4.0 prediction algorithm (Steentoft C et al. 2013) for O-glycosylation and the sulfinator tool for tyrosine sulfation sites (Monigatti F et al. 2002), suggest that CC chemokine receptors have general patterns of O-glycosylation and tyrosine sulfation in their N-terminal region which seem to be widely conserved between human and murine sequences. GalNAc-type or mucin-type O-glycosylation is initiated by the transfer of Gal-NAc to a serine or threonine residue by polypeptide GalNAc-transferases (GalNAc-Ts) which is further elongated with the linkage of other monosaccharides (Schjoldager KT et al. 2020), and usually capped by a single sialic acid, although, in rare cases glycans can carry polysialylation (PolySia) (Mindler K et al. 2021). PolySia has been described for CCR7 where it specifically affects the recognition of CCL21 but not CCL19, interfering with dendritic cell trafficking (Kiermaier E et al. 2016). Other examples of O-glycosylation impact on chemokine receptors include the viral receptor US28 (Bagdonaite I et al. 2016) where O-glycosylation contributes to the differential binding to CC or CX3C chemokine (Casarosa P et al. 2005). CCR5 O-glycosylation, which is under investigation in this study, also plays a major role in promoting the interaction with CCL3 and CCL5, being also important for HIV infection (Bannert N et al. 2001). Tyrosine sulfation consists in the transfer of a sulfate group from the adenosine 3’-phosphate 5’-phosphosulfate (PAPS) donor to the hydroxyl group of a tyrosine residue of the protein chain (Seibert C and Sakmar TP. 2008) by tyrosine sulfotransferase 1 or 2 (TPST1/2). This PTM has been shown to be heterogeneous [Li X et al. 2018; Scurci I et al. 2021) and to improve the affinity of chemokines through the charge interactions between the negative sulfate groups in the N-terminus and the positively charged chemokines (Ludeman JP and Stone MJ. 2014). CCR5 sulfation has been also reported to play a key role in CCL3 and CCL5 binding (Bannert N et al. 2001) as well as to exist in heterogeneous forms inside the cell (Scurci I et al. 2021). The atypical chemokine receptor 2 (ACKR2), US28 and sphingosine-1-phosphate receptor 1 (S1PR1) also carry tyrosine sulfation sites in their N-termini that mediate ligand binding and signaling (Bannert N et al. 2001; Casarosa P et al. 2005; Gao J et al. 2003; Fieger CB et al. 2005). Probing the modulation of O-glycosylation and tyrosine sulfation on CCR5 and CCR1 function In this study engineered cell lines, inhibitors and mutagenesis approaches were performed to evaluate the effects of O-glycosylation and tyrosine sulfation modulation on the chemokine receptors CCR1 and CCR5 pharmacology. Both PTMs were shown to contribute to the binding of CCL5 and CCL8 and to a minor extend CCL3. The interplay between these PTMs was also revealed where mutagenesis of tyrosine sulfation sites considerably impacted O-glycosylation. Removal of the terminal sialic acid was also shown to negatively impact signaling as previously appreciated (Bannert N et al. 2001). Interestingly, expression of PolySia was able to partially rescue the signaling upon reduction of sulfation, suggesting the fine-tuning role of O-glycosylation although the mechanism through which PolySia exerts its compensatory effect remains unclear. This effect could be driven by a specific carrier or it can potentially be related with the increase in the general negative charge of the cell surface glycosaminoglycans which have an established role in chemokine gradients and oligomerization (Deshauer C et al. 2015; Dyer DP et al. 2016). In this work authors set out to investigate GalNAc-Ts candidates involved in CCR5 O-glycosylation with CHO GalNAc-T knock-outs transfected with CCR5. From the five GalNAc-Ts, GalNAc-T1 was shown to be the most likely candidate for directly glycosylating CCR5 although T11 may also be involved. Sulfo-glyco barcode - perspectives and added value in drug discovery A growing body of evidence proposes that O-glycosylation and sulfation are important PTMs in chemokine receptor biology and pharmacology however the reported effects can vary depending on the receptor-ligand pairs and potentially cell line and tissue tested. The combined effects of both PTMs as well as the relevance of specific acceptor sites and glycan composition remains to be investigated in more depth. Dissecting the biological relevance of these PTMs requires relevant cells expressing the chemokine receptor endogenously together with relevant enzymes and co-receptor systems. In this study, although direct effects of O-glycosylation removal are ruled out it is possible that indirect effects may also contribute to the observed phenotype since many glycosyltransferases and the two TPSTs also carry O-glycosylation (King SL et al.2017). In addition, tyrosine sulfation is heterogenous between cell lines or even on the same cell (Scurci I et al. 2021). It remains to be discovered how much the modulation of these PTMs is relevant for future drug design. There are few examples of the applicability of the sulfo-glyco barcode in drug discovery. For CCR5, it has been shown that N-terminal antibodies show different sulfo-sensitivities (Scurci I et al. 2021). It has been also reported that PSGL-1 glycosulfo peptide analogue GSnP-6 displays nanomolar affinity and promising potential for blocking PSGL-1/P-selectin interaction (Wong DJ et al. 2021). Moreover, sulfated mCCR2 peptides can outcompete available chemokines, decreasing retinal degradation in mice (Jung SA et al. 2021). Further research will be needed to boost our understanding on the dynamics and biological relevance of these PTMs in the chemokine receptor system which may ultimately allow for new precise targeting of the immune system. Check the original article at https://pubmed.ncbi.nlm.nih.gov/36729338/ #GPCR #DrGPCR#Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. For Dr. GPCR News, please subscribe to our monthly newsletter. Below is your Classified GPCR News at a glance for February 6th to 12th, 2023. GPCR Activation and Signaling Ubiquitylation of BBSome is required for ciliary assembly and signaling. Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder. Unravelling GPCR signalling networks using global phosphoproteomics. GPCR Binders, Drugs, and more An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer. GPCRs in Neuroscience Heterotrimeric G proteins regulate planarian regeneration and behavior. Methods & Updates in GPCR Research Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency. Development and Characterization of a Highly Selective Turn-On Fluorescent Ligand for β3-Adrenergic Receptor. Quantitative analysis of sterol-modulated monomer-dimer equilibrium of the β1-adrenergic receptor by DEER spectroscopy. Industry News Biotech startup Structure pulls off rare IPO, raising $161M 3-drug combo leads to 'unprecedented' response in pancreatic cancer models Addex Therapeutics Ltd Strategic Partner Completes Enrollment in ADX71149 Epilepsy Phase 2 Study Part 1 IPO Raises $161M for GPCR-Based Drug Developer Structure Therapeutics Crinetics Pharmaceuticals Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) arcoscreen is one of the 13 biotech companies to discover in western in 2023 Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit, (February 21 - 23, 2023), Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). WEBINAR Using integrative biophysical approaches to understand GPCR regulation by β-arrestins. (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 B Building Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Director, Business Development & Strategy CADD and Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Fully Funded Doctoral Training Programme Studentships 2023 Computational drug design PhD student at the Department of Drug Design and Pharmacology Computational drug design postdoc at the Department of Drug Design and Pharmacology Software / database development PhD student at Department of Drug Design and Pharmacology Software / database development postdoc at the Department of Drug Design and Pharmacology Postdoc in Bioinformatics/Data Science at Department of Drug Design and Pharmacology Scientist/Senior Scientist (Research Software Engineer) Senior Scientist – Native Mass Spectrometry Speculative Applications (Protein Biochemistry) Speculative Applications (Mass Spectrometry) Speculative Applications (Chemistry) Post-Doctoral Research Assistant Research Fellow - School of Physics and Astronomy Postdoctoral Research Associate (Fixed Term) Explore Dr. GPCR Ecosystem

With around 187 people dying every day from an opioid overdose in the U.S., combatting the opioid overdose epidemic has become a mean challenge for the scientific community. According with the National Institute on Drug Abuse (NIDA) nearly 92, 000 Americans died from drug-involved overdose in 2020, of which approximately 75% involved opioids. Some examples of opioids include heroin, morphine, codeine, fentanyl, methadone, tramadol and other opioid analogs. Opioids are analgesic drugs consumed non-medically for euphoric feelings and medically for pain relief, although the last one comes with pharmacological side effects such as breathing difficulties and addiction which contribute to the current opioid crisis problem3. The opioid system is one of the most important in regulating the response to nociception, i.e. the response of the nervous system to painful stimuli; the 1970s marked the beginning of its study with the first discoveries which suggested that there were "binding sites" in the central nervous system that were recognized by exogenous opioids such as morphine, leading later to the discovery of opioid receptors1. The opioid system is composed of a set of major endogenous opioid peptides (EOPs): β-endorphin, enkephalins and dynorphins, and four opioid receptors (ORs): μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR) which are expressed throughout the central and peripheral nervous system and regulate important physiological functions such as analgesia, stress response, mood, reward, etc3. Opioid receptors belong to class A of G protein-coupled receptors or GPCRs and signaled mainly through Gai/o, beta/gamma subunits and arrestins. At the synapse, they are localized in both pre- and postsynaptic compartments and their activation is generally related to inhibiting neurotransmission by hyperpolarizing the cell or reducing or potentiating neuronal activity4. Given their pathophysiological significance in pain, addiction and depression opioid receptors represent important pharmacological targets. Morphine is one of the most widely used and proven analgesic for the treatment of severe acute or chronic pain conditions, but their use is overshadowed by their side effects and by the development of dependence and addiction. Morphine is an agonist of Mu opioid receptor (MOPR) and one of the objectives in the development of new opioids is to synthesize compounds with high analgesic power but without side effects like morphine does3. Therefore, the study of the different signal transductions triggered by the opioid-receptor interaction is of great importance. With this in mind one of the proposals is to take advantage of biased agonism, i.e. when the same receptor signals downstream through different signaling pathways triggered by different molecules2. There are several reports that have addressed the differences in the mechanisms of transduction triggered by MOR, reporting that G-protein signaling is more associated with the analgesic effect, while the side effects are orchestrated via β-arrestin 2. However, opioids that prevent recruiting β-arrestin 2 do not address the problem since ligands that only minimally recruit β-arrestin 2 to MORs may also cause opioid side effects2. Therefore to understand better the functions of arrestins in MOR signaling, Shiraki et al., explored the function of β-arrestin 2 in MOR signaling using the SH-SY5Y cell line that endogenously expresses MOR and was modified through CRISPR/Cas9 to knock out β-arrestin 1 and 2 gene expression. This report highlights a mechanism of β-arrestin pathway activation dependent on G protein activation, which contrasts with the idea that these signaling pathways are independent and compete with each other. The authors found that both β-arrestin 1 and 2 are involved in MOR internalization and downstream signaling activation of the β-arrestin pathway under Gi/o activation-MOR, being crucial the formation of β-arrestin/ β2-adaptin and clathrin heavy chain complex to mediates MAPK signaling5. These findings highlight how G proteins and β-arrestins are involved in driving intracellular signaling and reinforce the role of β-arrestins in the physiological opioid system. If you are interested in learning more about the molecular details of this study, you can consult the article at the following link https://pubmed.ncbi.nlm.nih.gov/36502633/ References 1. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5391-3. doi: 10.1073/pnas.90.12.5391. PMID: 8390660; PMCID: PMC46725. https://pubmed.ncbi.nlm.nih.gov/35435616/ 2. Faouzi A, Varga BR, Majumdar S. Biased Opioid Ligands. Molecules. 2020 Sep 16;25(18):4257. doi: 10.3390/molecules25184257. PMID: 32948048; PMCID: PMC7570672. https://pubmed.ncbi.nlm.nih.gov/8390660/ 3. Manhapra A. Complex Persistent Opioid Dependence-an Opioid-induced Chronic Pain Syndrome. Curr Treat Options Oncol. 2022 Jul;23(7):921-935. doi: 10.1007/s11864-022-00985-x. Epub 2022 Apr 18. PMID: 35435616. https://pubmed.ncbi.nlm.nih.gov/35782382/ 4. Reeves KC, Shah N, Muñoz B, Atwood BK. Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain. Front Mol Neurosci. 2022 Jun 15;15:919773. doi: 10.3389/fnmol.2022.919773. PMID: 35782382; PMCID: PMC9242007. https://pubmed.ncbi.nlm.nih.gov/32948048/ 5. Shiraki A, Shimizu S. The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor. Biochem Biophys Res Commun. 2023 Jan 15;640:64-72. doi: 10.1016/j.bbrc.2022.11.098. Epub 2022 Nov 30. PMID: 36502633. https://pubmed.ncbi.nlm.nih.gov/36502633/

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. For Dr. GPCR News, please subscribe to your monthly newsletter. Below is your Classified GPCR News at a glance for January 30th to February 5th, 2023. GPCR Activation and Signaling The dual-function chemokine receptor CCR2 drives migration and chemokine scavenging through distinct mechanisms. Cannabinoid 1 (CB1 ) receptor arrestin subtype-selectivity and phosphorylation dependence. Metabolic depletion of sphingolipids inhibits agonist-induced endocytosis of the serotonin1A receptor. Genetic code expansion to enable site-specific bioorthogonal labeling of functional G protein-coupled receptors in live cells. Platelet P2Y1 receptor exhibits constitutive G protein signaling and β-arrestin 2 recruitment. Multiple Potassium Channel Tetramerization Domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling. GPCR Binders, Drugs, and more Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1). Pharmacological characterization of novel small molecule agonists and antagonists for the orphan receptor GPR139. Valorization of leftover green tea residues through conversion to bioactive peptides using probiotics-aided anaerobic digestion. Comparative evaluation of biased agonists Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II (SD Ang II) and Sarcosine1 , Isoleucine8 -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors. GPCRs in Cardiology, Endocrinology, and Taste Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure. GPCRs in Oncology and Immunology LP2, a cyclic angiotensin-(1-7) analog extended with an N-terminal D-lysine, impairs growth of patient-derived xenografts of colorectal carcinoma in mice. Simultaneous activation of CXC chemokine receptor 4 and histamine receptor H1 enhances calcium signaling and cancer cell migration. Methods & Updates in GPCR Research Deep-Learning-Enhanced Diffusion Imaging Assay for Resolving Local-Density Effects on Membrane Receptors. Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin. Functional expression of oxytocin receptors in pulp-dentin complex. Reviews, GPCRs, and more Understanding Neuropeptide Transmission in the Brain by Optical Uncaging and Release. Patching holes in the mechanism of opioid tolerance. Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms, functions, and therapeutic targets. β-arrestins and G protein-coupled receptor kinases in viral entry: A graphical review. Development and challenges in the discovery of 5-HT1A and 5-HT7 receptor ligands. Involvement of SAP97 anchored multiprotein complexes in regulating cardiorenal signaling and trafficking networks. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. The Memory Orchestra: Contribution of Astrocytes. Structural and Molecular Insights into GPCR Function Structural view of G protein-coupled receptor signaling in the retinal rod outer segment. Cryo-EM structure of orphan G protein-coupled receptor GPR21. Industry News Exscientia Announces First-in-Human Study for Bristol Myers Squibb In-Licensed PKC Theta Inhibitor, EXS4318 GPCR Therapeutics Announces Launch of US Phase 2 Trial of GPC-100 in Multiple Myeloma Behind Friday's $161M IPO: A star scientist, GPCR drug discovery and a plan to challenge pharma in diabetes TGA’s approval of MDMA and Psilocybin for medical use is a result of ‘renewed interest’ Addex Strategic Partner Completes Enrollment In Adx71149 Epilepsy Phase 2 Study Part 1 Domain Therapeutics to Participate in Upcoming Investor and Industry Conferences International Day of Women and Girls in Science Orion Biotechnology Publishes Whitepaper Highlighting the Importance and Challenges in Unlocking “Undruggable” GPCRs Endocrine Society Awards Baxter Prize to Innovator in Endocrine Drug Discovery Upstream Bio Announces the Appointment of Marcella Ruddy, M.D., to the Board of Directors Call for GPCR Papers GPCRs: Signal Transduction. Deadline extended to March 31st, 2023 GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit, (February 21 - 23, 2023), Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). WEBINAR Using integrative biophysical approaches to understand GPCR regulation by β-arrestins. (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 B uilding Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Computational drug design PhD student at the Department of Drug Design and Pharmacology Computational drug design postdoc at the Department of Drug Design and Pharmacology Software / database development PhD student at Department of Drug Design and Pharmacology Software / database development postdoc at the Department of Drug Design and Pharmacology Postdoc in Bioinformatics/Data Science at Department of Drug Design and Pharmacology Scientist/Senior Scientist (Research Software Engineer) Senior Scientist – Native Mass Spectrometry Speculative Applications (Protein Biochemistry) Speculative Applications (Mass Spectrometry) Speculative Applications (Chemistry) Post-Doctoral Research Assistant Research Fellow - School of Physics and Astronomy Postdoctoral Research Associate (Fixed Term) Explore Dr. GPCR Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings Below is your Classified GPCR News at a glance for January 23rd to the 29th, 2023. GPCR Activation and Signaling A multi-dimensional view of context-dependent G protein-coupled receptor function. The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria. Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation. Molecular Modeling Study of a Receptor-Orthosteric Ligand-Allosteric Modulator Signaling Complex. GPCR Binders, Drugs, and more MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R. Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB1 and CB2 receptors. Methods & Updates in GPCR Research Development and Characterization of a Highly Selective Turn-On Fluorescent Ligand for β3-Adrenergic Receptor. GPCR Signaling Measurement and Drug Profiling with an Automated Live-Cell Microscopy System. Generation of Gαi knock-out HEK293 cells illuminates Gαi-coupling diversity of GPCRs. Reviews, GPCRs, and more Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target. Structural and Molecular Insights into GPCR Function Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor. Structural Understanding of Peptide-Bound G Protein-Coupled Receptors: Peptide-Target Interactions. Structural and Molecular Determinants for Isoform Bias at Human Histamine H3 Receptor Isoforms. Industry News Inversago Pharma to Participate at the 2023 SVB Securities Global BioPharma Conference Orbit Discovery and Endevica Bio enter multi-target collaboration to advance development of cachexia therapeutics Sosei Heptares Webinar Presentation for FY2022 Financial Results Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit, (February 21 - 23, 2023), Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Scientist/Senior Scientist (Research Software Engineer) Senior Scientist – Native Mass Spectrometry Speculative Applications (Protein Biochemistry) Speculative Applications (Mass Spectrometry) Speculative Applications (Chemistry) Post-Doctoral Research Assistant Research Fellow - School of Physics and Astronomy Postdoctoral Research Associate (Fixed Term) PhD Project - Investigating the lipid regulation of GPCR signalling Postdoctoral Fellow - Molecular Dynamics Postdoc in lipid regulation of GPCRs Postdoctoral positions, biophysics of transporters and GPCRs Chief of Staff Postdoctoral Fellow, Biochemical And Cellular Pharmacology Project Leader, Biology Explore Dr. GPCR Ecosystem

Executive Summary This whitepaper will provide an overview of G Protein-Coupled Receptors (GPCRs) and discuss current trends in GPCR drug discovery. GPCRs are an important class of drug targets that represent approximately 30% of global drug market sales. However, the receptors that these medicines target have been described as the ‘low-hanging’ fruit, and many of the remaining GPCRs have shown low tractability using established drug discovery approaches. This situation is now evolving, with recent scientific and technological breakthroughs encouraging a new wave of GPCR drug discovery. Among the challenging GPCRs are approximately 50 that have large natural ligands. While these small protein GPCRs are valuable drug targets linked to serious diseases, many remain undrugged because they are less tractable to standard drug discovery approaches. To solve this industry-wide problem, Orion Biotechnology (Orion) is introducing a novel solution driven by its PROcisionXᵀᴹ platform: precision-engineering analogs based on the natural small protein ligands of these receptors to unlock their therapeutic potential. The GPCR Opportunity GPCRs are the largest and most diverse group of membrane receptors. They are composed of seven membrane-spanning α-helices, comprising the transmembrane (TM) domain of the receptor, joined by alternating intracellular and extracellular loop regions that form the intracellular and extracellular faces of the receptor. In general, signaling occurs when agonists engage key microswitch structures located in the TM domain. These interactions induce local conformational changes which are amplified and transmitted to the intracellular face of the receptor, leading to the binding and activation of cytosolic effector proteins: the G proteins after which GPCRs are named, and arrestins which both shut off G protein activity and elicit G protein-independent signaling pathways. There are approximately 800 human GPCRs in the superfamily, controlling a broad range of physiological activities. Roughly half of the receptors in the superfamily are sensory GPCRs, involved in olfaction, taste, vision and pheromone signaling. The remaining non-sensory receptors, with functions more readily linked to pathology, are currently the main focus for GPCR drug discovery. A New Wave of GPCR Drug Discovery GPCRs are considered highly druggable, with GPCR-targeting therapeutics contributing ~30% of global drug market sales. However only ~15% of the GPCR superfamily has been successfully drugged, due in part to the intractability of certain groups within the GPCR superfamily to standard drug discovery approaches. Spurred on by new scientific and technological advances related to the understanding of structure and activation mechanisms of GPCRs, the biotech investment community has injected significant funding into small biotech companies developing novel technology platforms to target GPCRs in recent years. Within the last two years, three investments stand out: · Tectonic Therapeutics: received $80 Million USD in Series A financing to develop GPCR-targeting nanobodies. · Septerna: closed a $100 Million USD Series A round to develop small molecule drugs against difficult-to-drug GPCRs. · Domain Therapeutics: completed a $42 Million USD Series A round to develop novel immunotherapies, including an anti-CCR8 antibody. Small Protein GPCRs are Difficult to Drug Among the GPCRs that are challenging to drug using standard approaches is a group of approximately 50 receptors whose endogenous ligands are small proteins. These receptors have much larger binding pockets than the majority of GPCRs that have been successfully drugged so far. The significantly increased surface area of ligand-receptor interface for these GPCRs makes modulation with small molecule drugs, when they can be identified, much more challenging. Firstly, small molecule inhibitors only occupy a fraction of the available surface area in the large binding pocket, making them unsuitable for achieving full blockade of the natural ligand. Secondly, because the activation mechanism of small protein GPCRs involves making key contacts with the receptor at structurally distant sites in the binding pocket, it is difficult to achieve a high level of control over the quantity and quality of signaling activity using small molecule agonists. Significant resources have been invested into the search for small molecule modulators of small protein GPCRs, but discovery is challenging and the attrition rate during clinical development has been very high. Developing Small Protein Therapeutics with a Novel Discovery Platform One way to overcome the challenges presented by small protein GPCRs is to use small proteins as modalities to target them. These approaches include generating ligand analogs by precision engineering the natural small protein ligand of the receptor. The natural ligand of the target receptor provides an excellent scaffold, already with a size and shape that matches its binding pocket. The engineered analog approach involves optimizing this scaffold, adding and subtracting molecular contacts between the ligand and the receptor to obtain the required potency and signaling output. Small protein GPCRs feature a two-component binding mechanism in which one part of the ligand engages the extracellular face of the receptor, providing an ‘address’ function: binding affinity and specificity. The other part of the ligand reaches in to contact the TM domain of the receptor, providing a ‘message’ function: engaging the microswitches that control signaling activity. As seen below in Figure 1, natural ligands do not make use of all the potential binding contacts with the TM domain of the receptor, and by modifying these key points of contact it is possible not only to strongly increase binding affinity but also to fine tune both the quantity and quality of receptor signaling. Figure 1. Left: Natural ligands of small protein GPCRs use a two-component binding mechanism, with extracellular domain binding providing a highly specific ‘address’ function, and the transmembrane domain binding making ‘message’ contacts that drive signaling activity. Right: Orion ligand analogs are engineered to optimize transmembrane domain providing significantly increased binding affinity and providing a means to control both the quantity and quality of signaling activity. Orion’s approach to engineering ligand analogs involves leaving the ‘address’ binding interface on the extracellular face of the receptor unchanged and searching for optimized interaction with the TM domain of the receptor. This characteristic provides a major advantage in drug discovery: massive parallel library-based screening can be carried out directly on living cells expressing the target receptor. The unmodified ‘address’ interaction ensures that all molecules in the library are specific for the target receptor rather than irrelevant cell surface targets, meaning that in contrast to all of the other current GPCR discovery procedures, Orion’s approach does not require the onerous and time-consuming processes of target receptor expression, purification and stabilization at the beginning of a discovery campaign. Orion’s PROcisionXᵀᴹ Platform In Orion’s discovery process, shape space at the TM domain ‘message’ site is extensively explored by using surface display technology, with molecular diversity focused into the part of the ligand that engages the TM domain. Libraries of billions of analogs are screened in parallel for functional interaction with receptors presented in their physiological environment. Selection of the libraries typically leads to the isolation of several hundred candidate hits, enriched because they either bind with increased affinity at the cell surface, or because they have an enhanced capacity to elicit receptor internalization, thereby gaining the capacity to shelter inside the cell. Both properties enable enhanced ligands to avoid being eliminated during the stringent washing process. All candidate hits are then rapidly produced in parallel by total chemical synthesis using Orion’s proprietary multiplex synthesis technology, and then screened for pharmacological activity (receptor binding affinity, G protein and arrestin signaling) in high throughput cell-based assays. Screening directly identifies leads, and the structure-activity data obtained for the ensemble of candidate hits provides a rich resource of information to inform lead optimization, either by human and in silico-aided rational design, or by the construction of next-generation surface display libraries. The PROcisionXᵀᴹ platform (summarized in Figure 2) can be used to complete a discovery campaign within only 6-12 months, yielding optimized leads ready for preclinical validation. Hence PROcisionXᵀᴹ is one of the fastest discovery platforms in industry, and one that is uniquely capable of generating drug candidates with optimal molecular pharmacological properties for targeting small protein GPCRs. Figure 2: Workflow in Orion’s PROcisionXᵀᴹ platform. A unique and important feature of Orion’s discovery process is that the initial search for potent target receptor modulators is agnostic towards signaling activity because it selects for any kind of enhanced functional interaction with the receptor in the environment of a living cell. Since shape space exploration is specifically focused on the ‘message’ site in the TM domain, this means that lead candidates across the whole spectrum of signaling activity are identified: full antagonists, partial agonists with different levels of signaling activity, biased agonists that preferentially activate either G protein signaling or arrestin signaling, and superagonists with signaling activity higher than that of the native ligand (Figure 3). Figure 3: In a single discovery campaign (CCR5 is shown as an example), Orion’s PROcisionXᵀᴹ platform generates a diverse set of potent small protein ligand analogs across the whole spectrum of signaling activity. Orion has demonstrated that optimized antagonist analogs generated using the PROcisionXᵀᴹ platform have best-in-class in vitro functional inhibitory potency and show remarkably persistent binding. This leads to strikingly long in vitro receptor occupancy durations (at least seven days), meaning that lengthy pharmacodynamic activity is attained in vivo, despite the short circulatory half-life that is expected with small protein drugs. Orion’s receptor antagonist analogs have demonstrated powerful efficacies across a range of animal models spanning different disease indications. Orion’s superagonist analogs are not only powerful candidate drugs for receptor modulation in indications where potent receptor activation is required, they are also highly effective vehicles for payload delivery. This is due to their enhanced capacity to drive receptor internalization in a process that pulls the ligand, together with its conjugated payload, inside the target cell. Orion has demonstrated that this target cell-specific delivery cannot be achieved using the native ligand of the receptor, despite its modest level of receptor internalization activity (Figure 4). Figure 4: Payload delivery using Orion’s superagonist analogs on target cells expressing CCR5. The cytotoxic drug Monomethyl auristatin E (MMAE) was used alone or conjugated to either the native CCL5 ligand or to an Orion CCL5 superagonist analog. While the native ligand conjugate exhibited poor selectivity for CCR5-expressing cells and was less effective at killing cells than unconjugated MMAE, the Orion CCL5 superagonist analog significantly increased both the potency and selectivity of the payload towards target cells. Case study: Discovering a CCR2 Antagonist The chemokine receptor CCR2 regulates the recruitment of monocytes to the sites of inflammation. Since many inflammatory diseases are driven by inappropriate recruitment of monocytes into tissues, CCR2 has been described as the master controller of inflammatory pathology and is considered a valuable drug target for a number of inflammatory diseases including atherosclerosis, scleroderma, multiple sclerosis and cancer. Orion’s CCR2 antagonist analog (OB-004), discovered in only 6 months, is considerably more potent than the leading small molecule competitors in in vitro functional inhibition assays (Figure 5). In an ex vivo human endothelial transmigration model, OB-004 demonstrated an unprecedented level of monocyte blockade, robustly outperforming the most potent of the competitor small molecules (Figure 6). Orion used its discovery platform technology to rapidly develop a murinized version of OB-004 that was evaluated in a thioglycolate-induced peritonitis model. In this model, OB-004 showed powerful efficacy, achieving full blockade of monocyte recruitment in response to the inflammatory challenge (Figure 7). Figure 5: In an in vitro functional signaling assay on a human monocytic cell line, OB-004 demonstrated best-in-class potency versus a group of small molecule CCR2 inhibitors in clinical development. Figure 6: In a flow-based human monocyte endothelial transmigration assay, OB-004 strongly outperformed BMS813160 at all three concentrations tested, achieving full blockade of transmigration at the highest concentration in this stringent model. Figure 7: In vivo efficacy of murinized OB-004 (mOB-004) in the thioglycolate (TG) induced peritonitis murine model. Twice-daily treatment with mOB-004 dose-dependently suppressed monocyte infiltration into the peritoneum cavity, achieving complete blockade at the highest dose level. The Future of GPCR Research GPCRs are a very important class of drug targets, but despite historical successes, the majority of the superfamily remains undrugged, in part due to limitations in current drug discovery technology. There is a great deal of scientific and business interest in solving this problem, and the last two years have seen the emergence of a new wave of technology driven GPCR drug discovery companies. Available structural data across the GPCR superfamily is increasing at an exponential rate, alongside understanding of the mechanisms underlying receptor activation. This, together with the rapid development of artificial intelligence (AI)-driven in silico-based molecular interaction prediction, will inevitably lead to a more and more central role for in silico methodology and AI in GPCR drug discovery. Orion has entered a strategic research collaboration with Peptilogics, a US-based AI drug discovery company to exploit the rewards that can be reaped at this exciting new frontier. GPCRs with small protein ligands are among the receptor groups that have proven to be particularly challenging, and Orion has developed a unique and powerful solution to the problem, based on using the natural ligands of target receptors to generate precision-engineering analogs. Orion’s PROcisionXᵀᴹ platform has been validated by rapid success, obtaining not only best-in-class antagonists with strong in vivo efficacy, but also potent signaling molecules for indications where subtle tuning of receptor signaling is required, or as vehicles for payload delivery. In this way Orion has established itself as one of the leaders in the exciting new wave of GPCR drug discovery. About Orion Biotechnology Orion’s mission is to unlock the therapeutic potential of previously undruggable GPCRs. Orion has world-renowned expertise in GPCR pharmacology and protein engineering, and its proprietary drug discovery platform (PROcisionXᵀᴹ) has been used to rapidly and efficiently advance a diversified portfolio of GPCR-targeted drug candidates for the treatment of cancer and other serious diseases. Orion’s objectives include expanding internal and external pipelines and continuing to innovate technologies to unlock GPCRs. For more information, follow Orion Biotechnology on LinkedIn or visit www.orionbiotechnology.com. Relevant Publications Development of Orion’s platform technology Hartley, O. et al. (2004) Proceedings of the National Academy of Sciences of the United States of America, 101, 16460-16465. https://doi.org/10.1073/pnas.0404802101 · Initial work on precision engineering of a small protein GPCR ligand using new peptide chemistry technology and rational design Gaertner, H. et al. (2008). Proceedings of the National Academy of Sciences, 105(46), 17706–17711. https://doi.org/10.1073/pnas.0805098105 · Development and use of new technology to gain full control of signaling activity through a small protein GPCR via library-based screening Dorgham, K. et al. (2016) Methods in Enzymology, 570, 47-72. https://doi.org/10.1016/bs.mie.2015.09.014 · Library-based screening methodology for engineering small protein GPCR ligands Paolini-Bertrand, M. et al. (2018) The Journal of Biological Chemistry, 293(49), 19092–19100. https://doi.org/10.1074/jbc.RA118.004370 · New technology to rapidly synthesize candidate hits from library-based screening so that they can be tested in cell-based assays Akondi, K. B. et al. (2021) Chimia, 75(6), 489–494. https://doi.org/10.2533/chimia.2021.489 · Description of the fully integrated PROcisionXᵀᴹ discovery platform Structure-based validation of Orion’s approach Zheng, Y. et al. (2017) Immunity, 46, 1005-1017.e1005. https://doi.org/10.1016/j.immuni.2017.05.002 · Structural explanation of the receptor binding mechanism of a highly potent antagonist analog Isaikina, P. et al. (2021). Sci Adv, 7. https://doi.org/10.1126/sciadv.abg8685 · Structural explanation of the binding and activation mechanism of a highly potent superagonist analog In vivo efficacy validation of Orion’s optimized leads Lederman, M.M. et al. (2004) Science, 306, 485–487. https://doi.org/10.1126/science.1099288 · Use of a first precision-engineered analog to validate topical inhibition of CCR5 as a strategy for HIV prevention Veazey, R.S. et al. Journal of Infectious Diseases, 199, 1525-1527. https://doi.org/10.1086/598685 · Demonstration that topically administered precision engineered small proteins show full in vivo efficacy in a highly stringent model of HIV transmission Steinbach, K. et al. (2019) Science Translational Medicine, 11. https://doi.org/10.1126/scitranslmed.aav5519 · Demonstration of the in vivo efficacy of a systemically administered antagonist analog in a model of neuroinflammation Feasibility validation of Orion analogs in clinical development Cerini, F. et al. (2016) Protein Expression and Purification, 119, 1-10. https://doi.org/10.1016/j.pep.2015.10.011 · Demonstration of the feasibility of manufacturing clinical grade small protein analogs McGowan, I.M. et al. (2021). AIDS Res Hum Retroviruses, 37, 453-460. https://doi.org/10.1089/aid.2021.0010 · Successful first-in-human clinical study of a topically administered small protein analog The whitepaper can also be accessed at: https://fb-resources.fiercebiotech.com/free/w_defa3729/prgm.cgich=WP-Orion-02012023-WP

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings Below is your Classified GPCR News at a glance for January 16th to January 22th, 2023. GPCR Activation and Signaling Cornichon protein CNIH4 is not essential for mice gametogenesis and fertility. Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling. Cannabinoid tolerance in S426A/S430A x beta-arrestin 2 knock-out double mutant mice. Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation. The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model. Methods & Updates in GPCR Research Mapping of structural arrangement of cells and collective calcium transients: an integrated framework combining live cell imaging using confocal microscopy and UMAP-assisted HDBSCAN-based approach. First metabolic profiling of 4-n-nonylphenol in human liver microsomes by integrated approaches to testing and assessment: Metabolites, pathways, and biological effects. Reviews, GPCRs, and more Olfactory Receptors as an Emerging Chemical Sensing Scaffold. Structural and Molecular Insights into GPCR Function The role of G protein conformation in receptor-G protein selectivity. Targeting in silico GPCR conformations with ultra-large library screening for hit discovery. Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1). Industry News Addex Provides Corporate Update And Financial Guidance Structure Therapeutics Appoints Industry Leaders Eric Dobmeier and Joanne Waldstreicher to its Board of Directors GPCR Therapeutics launches multiple myeloma trial Salipro Biotech is attending the 3rd Advanced Therapy Showcase in Tokyo, Japan, organized by LINK-J Jounce takes the cash under amended deal with Gilead on anti-CCR8 antibody InterAx Biotech Announces the Appointment of Seasoned Pharmaceutical Executive, Dr. Christopher Prior, as CEO and Reports Recent Drug Discovery Highlights Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit, (February 21 - 23, 2023), Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Postdoctoral Fellow - Molecular Dynamics Postdoc in lipid regulation of GPCRs Postdoctoral positions, biophysics of transporters and GPCRs Chief of Staff Postdoctoral Fellow, Biochemical And Cellular Pharmacology Project Leader, Biology Explore Dr. GPCR Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. Below is your Classified GPCR News at a glance for January 9th to January 15th, 2023. GPCR Activation and Signaling New simulation insights on the structural transition mechanism of Bovine Rhodopsin activation. Mandibulofacial dysostosis with alopecia results from gain-of-ETAR function via allosteric effects on ligand binding. GPCR Binders, Drugs, and more Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design. Protease-activated receptor 2 (PAR2)-targeting peptide derivatives for positron emission tomography (PET) imaging. GPCRs in Cardiology, Endocrinology, and Taste Gender Differences in GRK2 in Cardiovascular Diseases and its Interactions with Estrogen. GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy. Reviews, GPCRs, and more Isolation and functional identification of secretin family G-protein coupled receptor from Y-organ of the mud crab, Scylla olivacea. Structural and Molecular Insights into GPCR Function Thermodynamic architecture and conformational plasticity of GPCRs. Structural Understanding of Peptide-Bound G Protein-Coupled Receptors: Peptide-Target Interactions. Cryo-EM structures of orphan GPR21 signaling complexes. GPCR Allostery: a View from Computational Biology. The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor. Industry News Trevena Enrolls First Subject in TRV045 Proof-of-Concept Trial Evaluating S1PR Mechanism of Action and Target Engagement Novo Nordisk's GLP-1 for Type II diabetes approved for first-line treatment The Lundbeck Foundation is awarding DKK 174 million in grants to seven ‘mind-bending’ research collaborations GPCR Therapeutics Announces Launch of US Phase 2 Trial of GPC-100 in Multiple Myeloma Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1). SLAS 2023 Building Biology in 3D Symposium. (April 20-21, 2023) SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd ERNEST Training School. (February 20 - March 3, 2023). GEM2023. (March 14-17, 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). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7). GPCR Jobs Biotechnology and Biological Sciences Doctoral Training Programme Senior QM Manager Director of Molecular Pharmacology, Discovery Biology Staff Scientist/Senior Staff Scientist, Disease Biology and Translational Sciences Senior Scientist, Drug Metabolism and Pharmacokinetics PhD Opportunity - Investigation Of The Role Of The Formyl Peptide Receptor 2 In Diabetic Retinopathy PhD Opportunity - Novel P2y Receptor Ligands For Drug Discovery Explore Dr. GPCR Ecosystem

Odorant receptors function and expression landscape Odorant receptors (ORs) belong to the G protein-coupled receptor (GPCR) family and are the largest known mammalian gene family with around 900 genes. ORs are highly expressed by olfactory sensory neurons of the nose where they are activated by different odorant molecules which initiate a neuronal response that drives odorant discrimination and perception (Young J. and Trask B. 2002). Higher-resolution analysis of gene expression, including q)RT-PCR, microarray, or relatively new NGS (RNASeq) analyses, have indicated that OR genes are also expressed in non-olfactory tissues including the testis, lung, intestine, skin, heart, and blood, where they can play diverse physiological roles. Although ORs expression is quite stable, the number of ORs expressed in different human tissues is highly variable from more than 60 ORs in the testis and only a few ORs in the liver (Flegel C. et al. 2013; Maßberg D. and Hatt H. 2018). OR4N4 is the most highly expressed OR in human spermatozoa and is an example of a highly and selectively expressed OR, whereas OR51E1 and OR51E2 represent ubiquitously expressed ORs, although there are highly increased in prostate tissue, especially in prostate cancer (Maßberg D. and Hatt H. 2018). Interestingly, olfactory neurons gene expression is very peculiar, and each neuron expresses a single OR gene however, ectopic ORs expression is unlikely to be modulated by this tight mechanism with transcriptomic analysis revealing that while the majority of cancer cells express multiple ORs, tumor cells associated with the nervous system express a single OR gene type (Kalra S. et. al 2020). Physiological functions of ectopically expressed olfactory receptors ORs participate in important cellular processes outside of olfactory system. In the cardiovascular system, ORs have the potential to operate as the main carriers of endogenously and exogenously derived odorants in our body. OR10J5 has been proposed to be a metabolic regulator of cardiac function (Jovancevic N. et. Al 2017) and its activation promotes migration and angiogenesis (Kim S. et. al 2015). In the immune system ORs are expressed in different blood cells where aroma compounds from butter, known ligands for a variety of class I ORs, induce chemotactic behavior in human neutrophils (Geithe C. et al. 2015). OR function has been implicated in myelogenous leukemia where OR2AT4 activation leads to reduced proliferation and enhanced apoptosis of acute myeloid leukemia cells (S Manteniotis et al. 2016). In the gastrointestinal system, ORs may significantly contribute to abnormal bowel functions. In the GI tract OR ligands drive an intracellular cascade that results in enhanced serotonin release (Braun T. et. al 2007), an important regulator of gut peristalsis. In the genito-urinary system, the activation of ORs was shown to influence the motility of spermatozoa (Spehr M. et. al 2003). In the human kidney ORs elicit intracellular Ca2+flux in renal proximal tubule cells via adenylyl cyclase (AC) activity (Kalbe B et. al 2016). OR51E1 and OR51E2, initially assumed to be GPCRs only expressed in prostate tissue, play a role in prostate cancer epithelial cells proliferation via activation by β-ionone which initiates prostate cancer cell cycle arrest (Jones S. et. al 2013). In the nervous system, although there is limited data, it has been suggested that ORs adopt functions in the central nervous system. For example, OR4M1 was proposed to interfere with aberrant tau hyperphosphorylation (Zhao W. et. al 2013). In the respiratory system, the activation of ORs by amyl butyrate and bourgeonal, OR2AG1 and OR1D2 agonists, respectively, impact the contractility of human airway smooth muscle cells (Kalbe B. et. al 2016). In non-small-cell lung cancer OR2J3 activation induced apoptosis and inhibited cell proliferation and migration in long-term stimulus experiments (Kalbe B. et al. 2017). In the skin, OR51E2 was shown to play a role in human melanocyte homeostasis (Gelis L. et. al 2016) and the sandalore-activated receptor OR2AT4 shown to promote human keratinocyte proliferation and migration (Busse D. 2014). Exploring ORs in drug discovery – opportunities and threats Given the functional relevance of ORs in different physiological and pathophysiological contexts, primarily based on the deorphanization of these receptors, with the identified ligands being often synthetic compounds, there has been a growing interest from the scientific community to target this class of GPCRs. However, selection of promising candidates is not an easy task. Due to the diversity of the OR family it will be critical to select potential targets to modulate in a disease setting as ectopic expression of ORs does not always correlate with functionality. In addition, most ORs require olfactory-specific chaperones to be correctly targeted to the surface of heterologous cells (Maßberg D. and Hatt H. 2018) which implies that heterologous expression of ORs is generally more technically challenging compared with expression of nonolfactory GPCRs and also that deorphanization is challenging. Finally, direct evidence that ectopically expressed OR drives pathophysiological processes remains a big bottleneck. In order to target ectopic ORs there is a need to identify selective agonists or antagonists, where the starting point can be using licensed drugs (for drug repurposing) and endogenous ligands. Odorants, the natural ligands, could potentially be used as ligands and particular forms of odorant delivery would be required where selectivity must be carefully evaluated as odoronts tend to bind to various ORs. Selective screening assays for ectopic ORs as well as investment on the structural characterization of these receptors would be of great help to aid drug discovery. The development of antibodies directed towards an OR could either drive receptor inactivation or activation of the receptor to destroy tumor cells or be used in drug delivery. The chimeric antigen receptor T cell therapy could also be a way to target tumor cells expressing ectopic ORs (Naressi R. et. al 2023). Future directions Important directions in ORs research to advance drug discovery include the deorphanization and characterization of relevant ligands, characterization of the function of ORs in vivo, development of in vitro systems for functional assays and the availability of structural information for structure-based drug design. Check the original article at https://pubmed.ncbi.nlm.nih.gov/35999088/ #GPCR #DrGPCR#Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. Below is your Classified GPCR News at a glance for January 2nd to January 8th, 2023. GPCR Activation and Signaling Signal Transduction and Gene Regulation in the Endothelium. Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target. GPCR Signaling Measurement and Drug Profiling with an Automated Live-Cell Microscopy System. GPCR Binders, Drugs, and more Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells. GPCRs in Neuroscience Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane. GPCRs in Oncology and Immunology Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway. Methods & Updates in GPCR Research Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs. Structural and Molecular Insights into GPCR Function Structural and functional analyses of a GPCR-inhibited ion channel TRPM3. Industry News Arcoscreen selected by START Lausanne to pitch at the START Global summit on the 23-24th March 2023. Twist Bioscience and Astellas Enter into Multitarget Antibody Discovery Research Collaboration Neurocrine Biosciences and Voyager Therapeutics Enter Strategic Collaboration for Development and Commercialization of Voyager’s GBA1 Program and Other Next-Generation Gene Therapies for Neurological Diseases Crinetics Pharmaceuticals To Present Corporate And Clinical Update At 41st Annual J.P. Morgan Healthcare Conference Neurocrine Biosciences, Inc.'s Director Stephen A. Sherwin Sells 30,000 Shares STALICLA signs agreement with Novartis on neurodevelopmental disorders Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. GPCR Jobs Biotechnology and Biological Sciences Doctoral Training Programme Senior QM Manager Director of Molecular Pharmacology, Discovery Biology Staff Scientist/Senior Staff Scientist, Disease Biology and Translational Sciences Senior Scientist, Drug Metabolism and Pharmacokinetics PhD Opportunity - Investigation Of The Role Of The Formyl Peptide Receptor 2 In Diabetic Retinopathy PhD Opportunity - Novel P2y Receptor Ligands For Drug Discovery Explore Dr. GPCR Ecosystem

Hello Readers👋, Happy New Year! We're excited to be back and share our weekly newsletter! We'll be sending it directly to your inbox every week, so you'll always be the first to know about the latest GPCR news. Below is your Classified GPCR News at a glance for December 19th to January 1st, 2023. GPCR Activation and Signaling Transactivation of receptor tyrosine kinases by purinergic P2Y and adenosine receptors. Ligand recognition and activation of neuromedin U receptor 2. Biased agonists differentially modulate the receptor conformation ensembles in Angiotensin II type 1 receptor. Unusual phototransduction via cross-motif signaling from Gq to adenylyl cyclase in intrinsically photosensitive retinalganglion cells. GPCR Binders, Drugs, and more Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency. Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders. Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor. GPCRs in Cardiology, Endocrinology, and Taste Metabolic depletion of sphingolipids inhibits agonist-induced endocytosis of the serotonin1A receptor. GPCRs in Neuroscience Role of G-Proteins and GPCR-Mediated Signalling in Neuropathophysiology. GPCRs in Oncology and Immunology Clinical, pathophysiologic, genetic and therapeutic progress in Primary Bilateral Macronodular Adrenal Hyperplasia. GPR4 in the pH-dependent migration of melanoma cells in the tumor microenvironment. Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19. Functional Assessment of Cancer-Linked Mutations in Sensitive Regions of Regulators of G Protein Signaling Predicted by Three-Dimensional Missense Tolerance Ratio Analysis. Deletion of macrophage Gpr101 disrupts their phenotype and function dysregulating host immune responses in sterile and infectious inflammation. Methods & Updates in GPCR Research Quantitation of Plasma Membrane (G Protein-Coupled) Receptor Trafficking in Cultured Cells. A robust antibody discovery platform for difficult-to-express G protein-coupled receptors. Reviews, GPCRs, and more Species dependence of A3 adenosine receptor pharmacology and function. Transcriptome profiling of male and female Ascaris lumbricoides reproductive tissues. Genetic Code Expansion To Enable Site-Specific Bioorthogonal Labeling of Functional G Protein-Coupled Receptors in Live Cells. Functional expression of oxytocin receptors in pulp-dentin complex. Ghrelin receptor signaling in health and disease: a biased view. Identification and expression analysis of G protein-coupled receptors in the cotton aphid, Aphis gossypii Glover. Structural and Molecular Insights into GPCR Function Global insights into the fine tuning of human A2AAR conformational dynamics in a ternary complex with an engineered G protein viewed by NMR. Fusarium graminearum Ste3 G-Protein Coupled Receptor: A Mediator of Hyphal Chemotropism and Pathogenesis. Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor. New insights into the structure and function of class B1 GPCRs. Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids. Tracking N- and C-termini of C. elegans polycystin-1 reveals their distinct targeting requirements and functions in cilia and extracellular vesicles. Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome: in silico protein structure analysis and molecular docking. Non-ionic cholesterol-based additives for the stabilization of membrane proteins. "Structural Clarity is Brought to Adhesion G protein Coupled Receptor Tethered Agonism". Surveying nonvisual arrestins reveals allosteric interactions between functional sites. Evaluating GPCR modeling and docking strategies in the era of deep learning-based protein structure prediction. Industry News Sosei Heptares and Neurocrine Biosciences won Out-Licensing Deal of the Year from Locust Walk Omass Therapeutics 2022 Review Sosei hooks millions from Eli Lilly alliance Septerna was selected as one of the Top Life Sciences Startups to Watch in 2023 by BioSpace Sosei Heptares Notes its Partner Tempero Bio has Received FDA Clearance to Advance Clinical Development of TMP-301 for Treatment of Alcohol and Substance Use Disorders AbbVie recruits a GPCR team in Oxford, buying out a fledgling biotech for $255M+ Domain Therapeutics announces first patient dosed with DT-9081 in phase I clinical study in patients with advanced, recurrent or metastatic solid tumors: the EPRAD study Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Hello Readers👋, We are working on bringing your the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for December 12 to December 18th, 2022. GPCR Activation and Signaling Molecular Mechanisms of PTH/PTHrP class B GPCR Signaling and Pharmacological Implications. GPCR Binders, Drugs, and more Persistent challenges in the development of an mGlu7 PAM in vivo tool compound: The discovery of VU6046980. Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic. GPCRs in Neuroscience Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain. GRK5 Deficiency in the Hippocampus Leads to Cognitive Impairment via Abnormal Microglial Alterations. GPCRs in Oncology and Immunology Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors. Methods & Updates in GPCR Research 3,4-Bis(hydroxymethyl)hexane-1,6-diol-based Maltosides (HDMs) for Membrane-Protein Study: Importance of Detergent Rigidity-Flexibility Balance in Protein Stability. iORbase: a database for the prediction of the structures and functions of insect olfactory receptors. GPCR Industry News Septerna Announces the Formation of a Cross-Functional Scientific and Drug Discovery Advisory Board Sosei Heptares and Lilly Enter Multi-target Collaboration and License Agreement in Diabetes and Metabolic Diseases Sosei Heptares Enters R&D Agreements with the University of Oxford and KU Leuven to Identify and Validate Key GPCRs Driving Gastrointestinal and Immune Disorders Inversago Pharma Doses First Patient in Phase 2 Trial of INV-202, an Oral, Peripherally-acting CB1 Inverse Agonist, in Patients with Diabetic Kidney Disease Chris Cargill, President and CEO, will present a company overview at the 41st Annual J.P. Morgan Healthcare Conference. Sosei Heptares' Partner Pfizer Progresses its Oral GLP-1 Receptor Agonist PF-07081532 into Phase 2 Clinical Trials for Treating Type 2 Diabetes and Obesity Special report 2022: Meet 20 women blazing trails in biopharma R&D ERNEST - 2022 Scientific Outputs Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Among the different families of G-protein-coupled receptors (GPCRs), adhesion GPCRs (aGPCRs) represent the second most abundant in humans. Structurally they characterize by a long extracellular region of adhesion-like domains which modulate protein-protein interactions; and also by the presence of the GPCR-Autoproteolysis INducing (GAIN) domain located upstream of the first transmembrane pass. As if its structure were not already complex enough, during their synthesis in the endoplasmic reticulum, many of these receptors are cleaved at the GPCR Proteolysis Site motif of the GAIN domain through an auto-catalysis process generating two peptides that are held together by non-covalent bonds during their transport to the membrane1. When I started studying aGPCRs, the structural conformation of the GAIN domain of ADGRL1/Lphn1 and ADGRB3/BAI3 was already known. These crystal structures showed how the Stalk region, which is a short peptide released from the GAIN during auto-proteolysis, has a β-lamin conformation and is held within the GAIN surrounded by numerous hydrophobic interactions1. However, at that time the structural conformation of the transmembrane (TM) region was not yet known. Fortunately, the scientific community has become increasingly interested in studying these proteins and this year the transmembrane structures of the aGPCRs ADGRL3/Lphn3, ADGRG1/GPR56, ADGRG5/GPR114, ADGRD1/GPR133, ADGRF1/GPR110, ADGRG2/GPR64, and ADGRG4/GPR112 were reported in their self-activating state, i.e. a unique activation model of aGPCRs where in the absence of the extracellular region the Stalk peptide functioning as an agonist (or also known as a tethered agonist) and adopts a hooked alpha-helix conformation within the transmembrane domains leading to receptor activation. The resolution of these Cryo-EM structures provided the basis for the mechanism of self-activation of aGPCRs supporting the encrypted ligand hypothesis that was put forward by the community before these structures were known2-6. As occurs with other GPCRs in an active state, in aGPCRs the rearrangements induced by the interaction of the Stalk sequence with the transmembrane regions promote their coupling with G-proteins. Different studies have shown that aGPCRs such as Lphns have promiscuous behavior, where in a constitutive state Lphns signal through different types of G proteins, so knowing the factors that determine the selectivity of coupling represents a very interesting area of research. Last month a very detailed paper analyzed the molecular mechanisms of the aGPCRs self-activation as well the selectivity of G-protein coupling using a mouse ADGRL3 receptor without extracellular region as a study model7. This paper proposes a series of molecular mechanisms that would be occurring during the self-activation of aGPCRs, some of which differ from those of GPCRs belonging other families, and I will tell you about some of their findings below. Through cell-based assays and Cryo-EM of high quality, it was possible to know that ADGRL3 can activate and form stable complexes with Gs, Gi, Gq, and G12, where like other GPCRs, the distal αH5 region of the G protein was needed to maintain an interface with the receptor core. Similar to Barros's 2022 report, which describes the Cryo-EM structure of human ADGRL3-G13, this paper reports that the stalk peptide of ADGRL3 adopts a hook conformation when binds to the binding pocket formed by TM1-3,5-7 and extracellular loop (ECL) 1,2,3. Furthermore, when an alignment analysis of the Stalk peptide of the aGPCR family was performed highlighted a new hydrophobic conserved motif composed of phenylalanine (F)/leucine (L) and methionine (M) which adopted a similar conformation in the ligand binding pocket and helps to stabilize the tethered ligand-receptor. Comparison between a predicted model of inactive receptor structure and self-activated Cryo-EM highlighted that outward movement of TM6 (a signature of GPCR activation), sharp bending of TM6, and tilting of TM7 and TM1 are characteristic of ADGRL3 self-activation. Interestingly, it was also reported that rearrangements of the TMs lead to a group of five hydrophobic amino acids present in TM1, 3, 5 and 7 forming a horizontal plane that helps to stabilize the self-active conformation of ADGRL3. Finally a comparative close analysis of the different Cryo-EM receptor structures with Gq, Gs, Gi and G12 showed that Gq/Gs have a similar mode of receptor binding, while Gi/G12 use a different engagement mechanism. Overall the count of interactions between the last eight αH5 residues of each G protein with the receptor showed that there are more polar interactions in Gq/Gs engagements than in G1/G12 engagements; where Gi had the fewest hydrophobic and polar interactions with the receptor and the αH5 tilt of G12 towards TM3/TM5 of the receptor is more pronounced compared to the rest of the G proteins. From a structural perspective, the -4 position of αH5 was key for the selectivity of G-protein coupling, since the change of amino acids in positions close to this position favored signaling toward a specific G-protein, which is interesting in biased signaling purposes. In view of the above, these new findings clearly demonstrate part of the molecular mechanisms involved in the self-activation of aGPCRs and open new perspectives for the community to formulate strategies to help modulate the activation and signaling of these receptors, particularly with a pharmacological approach. Indeed, despite their broad physiological importance in normal and pathological processes, so far no drugs have been approved that target any aGPCR. Check the original article at https://pubmed.ncbi.nlm.nih.gov/36309016/ Bibliography 1. Araç, D., et al., A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. Embo j, 2012. 31(6): p. 1364-78. 2. Barros-Álvarez, X., et al., The tethered peptide activation mechanism of adhesion GPCRs. Nature, 2022. 3. Ping, Y.-Q., et al., Structural basis for the tethered peptide activation of adhesion GPCRs. Nature, 2022. 4. Qu, X., et al., Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1. Nature, 2022. 5. Xiao, P., et al., Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature, 2022. 6. Boucard, A.A., Self-activated adhesion receptor proteins visualized. Nature, 2022. 604(7907): p. 628-630. 7. Qian, Y., Ma, Z., Liu, C., Li, X., Zhu, X., Wang, N., Xu, Z., Xia, R., Liang, J., Duan, Y., Yin, H., Xiong, Y., Zhang, A., Guo, C., Chen, Z., Huang, Z., & He, Y. (2022). Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling. Molecular cell, 82(22), 4340–4352.e6.

Hello Readers👋, Get the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for December 5 to December 11th, 2022. GPCR Activation and Signaling Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms, functions, and therapeutic targets Constitutive activity of the dopamine receptor D5R, highly expressed in CA1 hippocampal neurons, selectively reduces CaV 3.2 and CaV 3.3 currents GPCR Binders, Drugs, and more LP2, a cyclic angiotensin-(1-7) analog extended with an N-terminal D-lysine, impairs growth of patient-derived xenografts of colorectal carcinoma in mice Methods & Updates in GPCR Research Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor Reviews, GPCRs, and more Life, death and resurrection of plant GPCRs Structural and Molecular Insights into GPCR Function Synergistic and Competitive Lipid Interactions in the Serotonin 1A Receptor Microenvironment Industry News Addex and Indivior Extend Research Term Of Substance Use Disorder Gabab Positive Allosteric Modulator Discovery Collaboration Domain Therapeutics strengthens Scientific Advisory Board with appointment of immuno-oncology experts More millions roll in for Sosei Heptares Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023. Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. ERNEST GPCR early career investigator (ECI) Zoominar Survey 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Hello Readers👋, We are working on bringing your the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for November 28 to December 4th, 2022. Adhesion GPCRs GPR56 C-terminal fragment mediates signal received by N-terminal fragment of another adhesion GPCR Latrophilin1 in neurons. GPCR Activation and Signaling Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers. FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury. Distal extracellular teneurin region (teneurin C-terminal associated peptide; TCAP) possesses independent intracellular calcium regulating actions, in vitro: A potential antagonist of corticotropin-releasing factor (CRF). Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity. Mechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signaling. Virtual screening yields refined GPCR agonists. GPCR Binders, Drugs, and more Altered signaling at the PTH receptor via modified agonist contacts with the extracellular domain provides a path to prolonged agonism in vivo. GPCRs in Cardiology, Endocrinology, and Taste Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the β6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families. Quantification of changes in human islet G protein-coupled receptor mRNA expression in obesity. Alterations in mouse visceral adipose tissue mRNA expression of islet G-protein-coupled receptor ligands in obesity. The Ca2+/CaM, Src kinase and/or PI3K-dependent EGFR transactivation via 5-HT2A and 5-HT1B receptor subtypes mediates 5-HT-induced vasoconstriction. GPCRs in Neuroscience CGRP physiology, pharmacology, and therapeutic targets: Migraine and beyond. Emerging approaches for decoding neuropeptide transmission. Exploring pharmacological inhibition of Gq/11 as an analgesic strategy. Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression. Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family. GPCRs in Oncology and Immunology Germinal Center-Related G Protein-Coupled Receptors in Antibody-Mediated Autoimmune Skin Diseases: from Basic Research to Clinical Trials. Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells. Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation. Methods & Updates in GPCR Research CPGL: Prediction of Compound-Protein Interaction by Integrating Graph Attention Network With Long Short-Term Memory Neural Network. Establishment of a CaCC-based Cell Model and Method for High-throughput Screening of M3 Receptor Drugs. High-performance optical control of GPCR signaling by bistable animal opsins MosOpn3 and LamPP in a molecular property-dependent manner. A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant. Genetically encoded tools for in vivo G-protein-coupled receptor agonist detection at cellular resolution. Reviews, GPCRs, and more The diversity of invertebrate visual opsins spanning Protostomia, Deuterostomia, and Cnidaria. Structural and Molecular Insights into GPCR Function Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin. Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1) and its interactions with antagonist and agonist ligands. Cryo-EM structure of G-protein-coupled receptor GPR17 in complex with inhibitory G protein. Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor. Molecular insights into the mechanism of sugar-modified enkephalin binding to opioid receptors. Oligomerization of the heteromeric γ-aminobutyric acid receptor GABAB in a eukaryotic cell-free system. Call for GPCR Papers GPCRs: Signal Transduction Advances in Computational and Chemical Methods to study GPCR Signal Transduction. Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Transmembrane domains of GPCR dimers – a novel hot spot for drug discovery G-protein-coupled receptors (GPCRs) can form biologically active homodimers or heterodimers which drive specific signaling pathways that can modulate both physiological and pathological functions. GPCR dimers are therefore emerging drug targets in different therapeutic areas including depression, hypertension, diabetes, and vascular dementia (A. Faron-Gorecka, et al. 2019). In this study Xin Cai et al. highlight the importance of GPCR dimers in drug discovery referring to important conformational changes, allosteric properties, ligand and functional selectivity. But what are the conformation changes that drive GPCR dimerization? The interaction between two receptors in a dimer involves a conformational change in the transmembrane domain (TMD), with the most compelling studies revealing that the transmembrane helices TM4 and TM5 on one hand, and TM1 and TM7 on the other hand, form possible dimerization interfaces (Ploier, B. et al. 2016; Dijkman, P. M. et al. 2018; Manglik, A. et al. 2012). Interestingly, the amplitude of the conformational changes due to ligand binding is limited at these interfaces. An important example of a GPCR forming both monomers and dimers with distinct functions in respect to ligand binding, receptor activation, desensitization and trafficking is the apelin receptor (APJ) (Y. Li, et al 2012; B. Bai, et al. 2014; B. Ji, et al. 2020; L. Wan, 2020). APJ receptors form both homodimers and heterodimers with other members of the class A GPCR family such as with bradykinin 1 and 2 receptors (B. Bai et al. 2014; B. Ji et al., 2020). GPCR dimers are very attractive molecular entities since they have been found to drive biased signalling. Various studies reported that the biased properties of ligands and receptors are a consequence of GPCR dimer formation, where the dimer corresponds to the biased receptor. Junke Liu et al. recently provided key insights into GPCR oligomerization and biased signalling, using PAFR as a model, showing that stabilization of PAFR oligomers promotes G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. How dynamic are GPCRs dimer interfaces? GPCRs constantly bind to form dimers and dissociate to form monomers. GPCRs dimers exist in a transient state however they are still able to be activated and interact with G proteins and therefore preserve their physiological functions, an important observation when considering them as potential targets. Different models of dimer formation have been described for different receptors such as the ‘rolling dimer’ interface model in which multiple dimer conformations co-exist and interconvert (P.M. Dijkman et al., 2018). Structural insights into metabotropic glutamate receptors have shown that the dimerization interface is affected by the activation state of the receptors, with the interface mainly located at TM4 and TM5 when mGluR2 dimers are inactive, switching to an interface mainly at TM6 when the receptor is active (L. Xue, et al. 2015). What is the potential of targeting GPCR dimer interface in drug discovery? GPCR drugs efficacy usually depends on a pathway (G protein or β-arrestin), whereas side effects are normally mediated by another pathway (I. Mantas et al. 2022). Therefore, the biased properties of GPCR dimers comprise an opportunity to boost efficacy while reducing side effects. But how can we target GPCR dimers? Recent studies found that peptides derived from the transmembrane region of GPCRs can block the formation of dimers and alter their function by destroying the interface between two receptors (M. Gallo et al. 2022). An example is a peptide derived from TM5/TM6 of the cannabinoid CB1 receptor (CB1R) which has been shown to alter the structure of CB1R–5HT2AR heterodimers, preventing cognitive impairment while preserving analgesia in vivo (M. Gallo et al. 2021). A more in-depth analysis of the functional specificity of transmembrane peptides will provide a better understanding of the physiopathological role of GPCRs dimerization while accelerating drug discovery targeting GPCR dimers. Check the original article at https://www.sciencedirect.com/science/article/pii/S1359644622004123?via%3Dihub #GPCR #DrGPCR#Ecosystem

Historically, ligands for GPCRs have been identified before their receptor counterparts. With the cloning revolution, several unidentified receptors have been found and were labelled as “orphan” for their endogenous ligands. Orphan GPCRs have been shown to play key roles in various physiological functions, such as sensory perception, reproduction, development, growth, metabolism, and are also linked to major diseases, such as neuroinflammatory, metabolic and autoimmune diseases. Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance in order to better understanding human physiology as well as to dissect the molecular mechanism governing the involvement of these receptors in human pathology. GPR84 is an example of an orphan GPCR (Sharman et al., 2011), although it is widely accepted that medium‐chain fatty acids (MCFAs) can bind to and activate this receptor with modest potency. GPR84 is a Gi‐coupled class A GPCR mainly expressed in immune cells and microglia in the brain (Wojciechowicz & Ma'ayan, 2020). GPR84 has been shown to be an attractive target in pro‐inflammatory conditions (Gagnon et al., 2018; Suzuki et al., 2013; Vermeire et al., 2017; Wojciechowicz & Ma'ayan, 2020) and efforts have been made to discover GPR84 antagonists. In this study Marsango et al. address two key questions in GPR84 biology and pharmacology: 1. how GPR84 expression profile correlates with physiological and pathological conditions? and 2. which ligands can be used as tool compounds to study the function and biology of this receptor? Regarding the first question, GPR84 overexpression in immune cells in a range of pro‐inflammatory disorders renders it a promising target in inflammatory and fibrotic conditions, including neuroinflammation (Audoy‐Remus et al., 2015), with ongoing clinical trials in idiopathic pulmonary fibrosis (Labéguère et al., 2014). GPR84 has been additionally proposed to be a potential biomarker in different inflammatory diseases (Arijs et al., 2011; Planell et al., 2017). Some studies have also reported GPR84 involvement in pain, atherosclerosis, and even metabolic disorders (Nicol et al., 2015, Audoy‐Remus et al., 2015, Du Toit et al., 2018). Regarding the second question, there is still a lot to be done in respect to tool compounds to study the function of this receptor towards clinical validation, as well as radiopharmaceuticals, including potential PET ligands, and suitable antibodies. Recent work has shown distinct functional outcomes of agonist ligands (Pillaiyar et al., 2018) with biased properties which can help to better elucidate the molecular pharmacology of this receptor. In addition, several GPR84 ligands have been described as well as GPR84 knockout mice. Among these ligands are orthosteric agonists such as alkylpyrimidine‐4,6‐diol derivatives (Liu et al., 2016; Zhang et al., 2016) and embelin (2,5‐dihydroxy‐3‐undecyl‐1,4‐benzoquinone) which is a natural product derived from the plant Embelia ribes (Gaidarov et al., 2018) which agonizes GPR84 but, interestingly, blocks the chemokine receptor CXCR2 and the adenosine A3 receptor (Gaidarov et al., 2018). IM (3,3′‐methylenebis‐1H‐indole) has been identified as a positive allosteric modulator of GPR84, a metabolite produced in vivo from indole‐3‐carbinol, which is present at high levels in some vegetables including broccoli and kale (Wang, Schoene, Milner, & Kim, 2012, Köse et al., 2020). GPR84 antagonists include a series of dihydropyrimidinoisoquinolinones (Labéguère et al., 2014), which behave as non‐competitive antagonists of GPR84 (Labéguère et al., 2020). From these series of compounds, GLPG1205 progressed into clinical development for the potential treatment of ulcerative colitis although it did not demonstrate sufficient efficacy (Labéguère et al., 2020). Overall, GPR84 is a promising target to exploit and the investment in better tools to study its function in both disease and physiological settings will likely potentiate drug discovery campaigns against this orphan GPCR. Check the original article at here! #GPCR #DrGPCR#Ecosystem

What is the molecular basis that determines that GPCRs bind selectively or promiscuously to different G proteins?. This question led Huang et al., 2022 to investigate the molecular basis involved in G protein-receptor interactions, particularly the differences between Gs and Gi/o coupling. Through Cryo-Electron Microscopy, authors reported the structures of four protein complexes integrated by a complete human serotonin receptor subtype and a dominant negative form of Gs or Gi: 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. Prior to this report we did not know how different serotonin receptor subtypes which share high sequence homology, coupled to different families of G proteins, so the comparison and structural analysis of these complexes revealed two important aspects: the specific residues involved in ligand selectivity and the interactions involved in the coupling of G proteins. The binding pockets for serotonin were virtually identical between the receptor-Gs and receptor-Gi complexes, suggesting that the selectivity of the G-protein lies in intrinsic features of the receptor rather than in a serotonin-induced mechanism. The discovery of the orthosteric binding pocket is of great importance in GPCRs field as it supports the development of alternatives to improve drug design to optimize receptor selectivity. In the same way, as in other GPCRs-G protein complexes, the structural analysis revealed that electrostatic interactions are crucial for the coupling of G-proteins to serotonin receptors. The structural differences found between the receptor-Gs and receptor-Gi complexes evidenced that 5-HT4/6/7-Gs coupled receptors have a cytosolic TM5 that is on average 5.7 residues longer and a TM6 that is 7.5 residues shorter compared to 5-HT1/4 receptors that couple to Gi/o. The TM5 extension of receptors Gs-coupled provides unique interactions that are not seen in complexes formed with Gi. These differences are mainly attributed to the characteristic Ras domain distance between Gs and Gi. Therefore the authors propose that the relative lengths of TM5 and TM6 in serotonin receptors function as a macro-switch to determine the selectivity of coupling between Gs or Gi/o. Additionally, structural analysis of the TM5 and TM6 regions of 27 class A GPCRs coupled to Gs or Gi/o yielded similar results, TM5 was 5.6 ± 1.5 residues longer while TM6 was 2.6 ± 1.6 residues shorter, concluding that the TM5-TM6 macro-switch length is conserved in class A GPCRs. Likewise, in this work the authors identify for the first time the specific amino acids that modulate the selectivity of coupling to Gs and Gi/o, reporting the presence of conserved residues for each type of G protein. The differences found at the residue level are referred to as micro-switches that will define a selective or promiscuous coupling of the receptor to the G protein. Interestingly, in the case of promiscuous receptors they found that these receptors shared conserved residues of both G protein families, suggesting that receptors that activate both Gs and Gi/o do so by combining the properties of the conserved residues with a mixture of Gs and Gi/o specific properties. These findings contribute to progress in understanding how serotonin receptors, one of the largest subfamilies of class A GPCRs and potential therapeutic targets that are activated by the same endogenous ligand, create a wide diversity of cellular responses. Check the original article at this link https://pubmed.ncbi.nlm.nih.gov/35714614/ *Above information was taken from the original article published by Huang et al., 2022. #GPCR #DrGPCR

Every year, with the month of October, comes the excitement of the Nobel session to the global scientific community. In the first few weeks of the month, the Royal Swedish Academy of Sciences and the Nobel Assembly at the Karolinska Institute announce the winners of the Nobel prizes in Physics, Chemistry, and Physiology or Medicine, the most recognizable awards for the impact of scientific work carried out by scientists in these three fields. This recognition also acknowledges the relative importance of a particular scientific area received from the scientific community and the perceived impact the finding has had on human scientific progress. Therefore, the presentation of 10 or more Nobel prizes highlights the importance of research work on the GPCR-mediated signal transduction garnered in the human scientific enterprise. The first Nobel prize that can be attributed to work related to GPCR-mediated signaling was the 1947 Nobel Prize in Physiology or Medicine, awarded to Carl Ferdinand Cori, Gerty Theresa Cori (née Radnitz), and Bernardo Alberto Houssay for their discoveries related to how glycogen is broken down to glucose and resynthesized in the body for use as a store and source of energy. Through their Nobel prize-winning work, the Coris found that adrenaline, a nonselective agonist for all types of adrenergic receptors, decreases the amount of glycogen in the liver and muscles. [1-6] Houssay received this honor for his discoveries concerning the role of the various hormones, including adrenaline secreted from the anterior pituitary lobe, in carbohydrate metabolism and the onset of diabetes. In 1967, the Nobel Prize in Physiology or Medicine was awarded jointly to Ragnar Arthur Granit, Haldan Keffer Hartline, and George David Wald for their discoveries concerning the primary physiological and chemical visual processes in the eye.[7–11] Through Nobel prize-winning research work, Wald made important discoveries on the role that the class-A archetypical GPCR rhodopsin plays in scoptic vision and night blindness. In 1970, the Nobel Prize in Physiology or Medicine was awarded to Julius Axelrod, Bernard Katz, and Ulf Svante von Euler for their work on the release and reuptake of neurotransmitters in neural communication.[12–17] Katz's scientific studies involved the release of the neurotransmitter acetylcholine, whereas the studies by Axelrod and von Euler focused on the neurotransmitter norepinephrine. Norepinephrine exerts its effects by binding to α- and β-adrenergic receptors, while acetylcholine binds to nicotinic acetylcholine receptors and muscarinic acetylcholine receptors.[18] The 1971 Nobel Prize in Physiology or Medicine went to Earl Wilbur Sutherland Jr for discovering the key role of adenylate cyclase, which produces the archetypical secondary messenger cyclic AMP (cAMP), plays in cellular signaling.[20,21] Adenylate cyclase is a major component of the downstream signaling cascade of the cAMP signal pathway, one of the two principal signal transduction pathways associated with GPCRs mediated signaling.[19–23] The 1988 Nobel Prize in Physiology or Medicine went to George Herbert Hitchings, Sir James Whyte Black, and Gertrude Belle Elion for their discoveries of important principles for drug treatment.[24–30] Black was particularly interested in developing drugs that targeted GPCRs and was credited with discovering propranolol, an antagonist for ß-adrenergic receptors, and cimetidine, an antagonist for histamine H2 receptor.[31,32] The 1992 Nobel Prize in Physiology or Medicine was awarded to Edwin Gerhard Krebs and Edmond Henri Fischer for describing how reversible phosphorylation works as a switch to activate proteins and to regulate various cellular processes, including glycogenolysis.[33–39] In their work, the duo further investigated the work of Gerty Cori and Carl Cori on carbohydrate metabolism. Incidentally, phosphorylation is a key regulatory mechanism employed in the GPCR-mediated signal transduction, where signaling of most GPCRs via the G-protein-dependent pathway is terminated by the phosphorylation of active receptors by specific kinases. Moreover, the G protein-independent pathway is mainly regulated by arrestin, which recognizes and binds phosphorylated GPCRs. The 1994 Nobel Prize in Physiology or Medicine was awarded to Alfred Goodman Gilman and Martin Rodbell for their discovery of G-proteins and the role of these proteins in signal transduction in cells.[40–46] In his work, Rodbell demonstrated that signal transduction through the cell membrane involves a cooperative action of three different functional entities: (1) a discriminator or receptor, which binds the primary messenger, (2) a transducer that requires GTP, and (3) an amplifier that generates large quantities of a second messenger. Gilman discovered that the transducer component of signal transduction that requires GTP is G-protein and was the first to isolate it through his work on leukemia cells. G protein-dependent signaling is the most well-known mechanism employed in GPCRs mediated signal transduction.[47] The 2000 Nobel Prize in Physiology or Medicine went to Eric Richard Kandel, Arvid Carlsson, and Paul Greengard for research on signal transduction in the nervous system.[48–54] Carlsson won the prize for his discovery that dopamine is a neurotransmitter produced in the basal ganglia, a brain region involved in movement control. Dopamine exerts its action in the human nervous system via dopamine receptors and human trace amine-associated receptor 1 (hTAAR1). Greengard was recognized for his contributions to the elucidation of the signaling pathways by which neurotransmitters such as dopamine, noradrenaline, and serotonin control neuronal excitability.[55,56] He identified a number of signal transduction proteins, particularly kinases and phosphatases, that are involved in synaptic transmission[55,56] Kandel was honored for demonstrating that cellular signaling events such as ion channel conduction and synaptic neurotransmitter release are involved in "short-term memory", whereas cAMP signaling and new protein synthesis are required for "long-term memory". The 2004 Nobel Prize in Physiology or Medicine went to Richard Axel and Linda Brown Buck for their work on Class-A olfactory receptors.[57–61] The two jointly carried out work to discover that sensing smell involved a large number of relatively specific olfactory receptors that are structurally similar to rhodopsin. These odorant receptors (ORs) now account for about 60% of all identified human GPCRs. The most recent Nobel prize awarded for work relevant to GPCR-mediated signaling was the 2012 Nobel Prize in Chemistry to Brian Kent Kobilka and Robert Joseph Lefkowitz for their work on GPCR function.[62–66] Lefkowitz was able to isolate β-adrenergic receptors from tissue samples to carry out the first structure-function characterization studies on GPCRs. Later on, Kobilka joined in with Lefkowitz to identify the shared architecture of the β-adrenergic receptor with that of rhodopsin.[67] In 2011, Kobilka further contributed to the field by obtaining the first X-ray crystal structure of a GPCR bound to its signaling partner (β-adrenergic receptor bound to the partial inverse agonist carazolol).[67] In spite of these advancements, there is much more to be discovered regarding how GPCRs mediate signaling. Our understanding of how various factors, such as lipid composition, osmotic stress, and allosteric ligands, modulate the conformational dynamics of GPCRs remains crude. Much more need to be uncovered about bias signaling, tissue-specific GPCR activation profiles, compartmentalized GPCR signaling, and location bias.[68–70] Further, our understanding of cross-talk between GPCR-mediated signaling pathways with other cellular signaling pathways, as well as non-signaling roles of GPCRs, such as acting as transcription factors, are still in their infancy. Therefore, we envision that this field will continue to produce high-impact research work that will garner more accolades from the global scientific community and continue to make large scientific discoveries to the improvement of human well-being.[68–72] References: 1. The Nobel Prize in Physiology or Medicine 1947. https://www.nobelprize.org/prizes/medicine/1947/summary/. 2. 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November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

September 2022 "Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying mutations vary considerably. In this work, we utilize deep mutational scanning to quantitatively compare the plasma membrane expression of 123 known pathogenic rhodopsin variants in the presence and absence of the stabilizing cofactor 9-cis-retinal. We identify 69 retinopathy variants, including 20 previously uncharacterized variants, that exhibit diminished plasma membrane expression in HEK293T cells. Of these apparent class II variants, 67 exhibit a measurable increase in expression in the presence of 9-cis-retinal. However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations. Evaluation of the observed shifts relative to thermodynamic estimates for the coupling between binding and folding suggests underlying differences in stability constrains the magnitude of their response to retinal. Nevertheless, estimates from computational modeling suggest that many of the least sensitive variants also directly compromise binding. Finally, we evaluate the functional properties of three previous uncharacterized, retinal-sensitive variants (ΔN73, S131P, and R135G) and show that two of these retain residual function in vitro. Together, our results provide a comprehensive experimental characterization of the proteostatic properties of retinopathy variants and their response to retinal." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE