Hello GPCR people! We have great news! This week we’ve curated 18 GPCR papers, 1 new event, 9 industry news, and 3 job opportunities! Take a few minutes, and dive into our GPCR coverage! We welcome GPCR paper suggestions! Submit your publications to Hello@DrGPCR.com for consideration. This week's highlight: Thank you to Dr. Tobias Langenhan for his papers to highlight suggestions GAIN Domain Unfolding in Adhesion GPCRs Molecular Sensing in Adhesion GPCR Dissociation Physiological Force Modulation in Drosophila Neurons Dr. David Gloriam and his team present GproteinDb in 2024 Are you looking to hire? Or maybe looking for your next opportunity? Let Mark Schmeizl, our Chief Matchmaker help. Contact him by filling out this form. Our November Dr. GPCR Newsletter is now available. This month's video newsletter features Dr. Alix Rouault as our special guest. Subscribe now! Don't miss the upcoming episodes of Dr.GPCR Podcast featuring Dr. Neil Grimsey and Dr. Katarzyna Marcinkiewicz. Now check out the weekly Classified GPCR News from November 20th to 26th, 2023. Adhesion GPCRs The Posttraumatic Increase in the Adhesion of GPCR EMR2/ ADGRE2 to Circulating Neutrophils Is Not Related to Injury Severity Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation GPCR Activation and Signaling GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism The mechanism of Gαq regulation of PLCβ3-catalyzed PIP2 hydrolysis GPCR Binders, Drugs, and more Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays GPCRs in Oncology and Immunology RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment High Metabolite Concentrations in Portal Venous Blood as a Possible Mechanism for Microbiota Effects on the Immune System, and Western Diseases Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 Chemokine N-terminal-derived peptides differentially regulate signaling by the receptors CCR1 and CCR5 Chemokine Cxcl1-Cxcl2 heterodimer is a potent neutrophil chemoattractant Methods & Updates in GPCR Research GproteinDb in 2024: new G protein-GPCR couplings, AlphaFold2-multimer models and interface interactions Experimental modulation of physiological force application on leg joint neurons in intact Drosophila melanogaster Reviews, GPCRs, and more Catecholamine Derivatives: Natural Occurrence, Structural Diversity, and Biological Activity Advances in steroid research from the pioneering neurosteroid concept to metabolomics: New insights into pregnenolone function Molecular characterization of lumpy skin disease virus from recent outbreaks in Pakistan Structural and Molecular Insights into GPCR Function Structural and signaling mechanisms of TAAR1 enabled preferential agonist design Proteome-wide structural analysis quantifies structural conservation across distant species Industry News Avantor's (AVTR) New Offerings to Aid Cell and Gene Therapy Suite Avantor® Expands Cellular Science Offerings with Multispan Cell Engineering and Assay Services $3bn sales potential for drug Sosei Heptares wants back from GSK Novartis drops subpoena request in trade-secret spat with Takeda Novartis showcases significant data updates from Kisqali®, iptacopan and Scemblix® at SABCS and ASH Research reveals pro-phagocytic function and structural basis of GPR84 signaling Advancements in Precision Medicine: Superluminal Medicines Inc. Showcases Innovative AI-Driven Drug Design at BRIC AI 2023 Workshop Salipro Biotech AB Celebrates Milestones in CryoEM Structures and In Vitro Binding Assays Through Collaboration with Sanofi Genentech and NVIDIA Enter Into Strategic AI Research Collaboration to Accelerate Drug Discovery and Development GPCR Events, Meetings, and Webinars January 16 - 19, 2024 | 23rd Annual PEP Talk February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition NEW February 11 - 14, 2023 | 2024 BPS Annual Meeting March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting April 22 - 23, 2024 | Endocrine Metabolic GPCRs May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs - Contact Mark Schmeizl NEW Scientist NEW Lead Researcher NEW Post-Doctoral Fellow Sr Scientist in Obesity, Muscle, and Metabolism Post-Doctoral Fellow Research Associate I, Tissue Culture Post-Doc Research Associate Postdoctoral Fellow Explore Dr. GPCR Ecosystem

Hi there readers! This week we’ve curated 13 GPCR papers, 1 new event, 11 industry news, and 3 job offers! Check out our GPCR roundup now, and be the first to read! This week's highlight: Drs. Brian Krumm and Bryan Roth studied CryoEM structures of adhesion in GPCR CD97, filling gaps. Last Friday was our final Dr. GPCR Symposium for the year, focusing on GPCRs in Immunology and Oncology, concluding the Dr. GPCR Symposia 2023. We extend immense gratitude to our exceptional speakers and all attendees who participated. For those who joined any of our symposium sessions, we kindly request a moment of your time to fill out our survey. If you weren't able to attend, don't worry – our premium members have continuous access to revisit and watch the archived presentations at any time HERE. Sign up for Dr. GPCR Newsletter and stay ahead of the curve with news on the Dr. GPCR University live courses we are preparing for you in 2024. Now let’s dive into the weekly Classified GPCR News from November 13th to 19th, 2023. Adhesion GPCRs CryoEM structures of adhesion in GPCR CD97: Filling in some of the gaps GPCR Activation and Signaling Butyrate induces STAT3/HIF-1α/IL-22 signaling via GPCR and HDAC3 inhibition to activate autophagy in head kidney macrophages from turbot (Scophthalmus maximus L.) Endosomal signaling via cAMP in parathyroid hormone (PTH) type 1 receptor biology β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination GPCR Binders, Drugs, and more Dual allosteric and orthosteric pharmacology of synthetic analog cannabidiol-dimethylheptyl, but not cannabidiol, on the cannabinoid CB2 receptor GPCRs in Cardiology, Endocrinology, and Taste Transcriptomic changes in glomeruli in response to a high salt challenge in the Dahl SS rat GPCRs in Neuroscience Neurokinin-2 receptor negatively modulates substance P responses by forming complex with Neurokinin-1 receptor NTR-1's Essential Contribution to Asymmetric Mating Between Two Sibling Nematode Species: Bursaphelenchus xylophilus and B. mucronatus GPCRs in Oncology and Immunology GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis GPR56 signaling pathway network and its dynamics in the mesenchymal transition of glioblastoma Methods & Updates in GPCR Research Optogenetic Microwell Array Screening System: A High-Throughput Engineering Platform for Genetically Encoded Fluorescent Indicators Design of an effective small expression tag to enhance GPCR production in E. coli-based cell-free and whole cell expression systems A high-throughput structural dynamics approach for identification of potential agonists of FFAR4 for type 2 diabetes mellitus therapy Industry News OMass Therapeutics Welcomes Melissa Faris as Chief Business Officer Septerna: Revitalizing G-Protein Coupled Receptor Drug Discovery Orion’s VP Drug Discovery, Dr. Oliver Hartley, was at the PEGS Europe Novartis pays Legend $100M upfront to give solid tumor CAR-T the T-Charge treatment Innovation And Healthcare Meet At Novartis Neurocrine Biosciences Announces Settlement of INGREZZA Abbreviated New Drug Application (ANDA) Litigation PostEra Announces a Research Collaboration with Amgen to Discover Small Molecule Therapeutics using Artificial Intelligence Novo Nordisk Invests 42 Billion Danish Kroner in New Manufacturing Facilities Addex ADX71149 Epilepsy Phase 2 Study Completes Recruitment of Patients Sanyou Bio's Evolution of Bioprocess Enhancement for CHO Cell Lines: A Talk by Dr. Meiling Lim TRUQAP™ (capivasertib) plus fulvestrant approved in the US for patients with advanced HR-positive breast cancer GPCR Events, Meetings, and Webinars November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting January 16 - 19, 2024 | 23rd Annual PEP Talk February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry NEW April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting April 22 - 23, 2024 | Endocrine Metabolic GPCRs May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Sr Scientist in Obesity, Muscle, and Metabolism NEW Post-Doctoral Fellow NEW Research Associate I, Tissue Culture Post-Doc Research Associate Postdoctoral Fellow Research Scientist/Postdoctoral Associate in Computational Chemistry/Biophysics Post-Doctoral Associate Team Leader Antibody Discovery Explore Dr. GPCR Ecosystem

Hi, everyone! This week, we've curated 12 GPCR papers. Plus, don't miss out on 6 upcoming events, 2 new job offers, and 9 industry updates. Let’s dive in! Save the date: TOMORROW - November 17: Don't miss out on our final Dr. GPCR Symposium for the year, which will focus on GPCRs in Immunology and Oncology. A panel of top experts will be discussing this topic in a roundtable, starting at 10:00 AM EST. You can find more details about the speakers on the Live Talks page, and make sure to mark your calendar for this important event! Discover the latest monthly Dr. GPCR Newsletter with Dr. Kathleen Caron, as our video guest, subscribe now! Now check out the weekly Classified GPCR News from November 6th to 12th, 2023. GPCR Activation and Signaling Neuronal survival factor TAFA2 suppresses apoptosis through binding to ADGRL1 and activating cAMP/PKA/CREB/BCL2 signaling pathway Deciphering specificity and cross-reactivity in tachykinin NK1 and NK2 receptors GPCR Binders, Drugs, and more Discovery of (S)-3-(4-(benzyloxy)phenyl)-2-(2-phenoxyacetamido)propanoic acid derivatives as a new class of GPR34 antagonists Larixol is not an inhibitor of Gαi containing G proteins and lacks effect on signaling mediated by human neutrophil expressed formyl peptide receptors Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2 GPCRs in Cardiology, Endocrinology, and Taste Lack of HCAR1, the lactate GPCR, signaling promotes autistic-like behavior Acetate mitigates cardiac mitochondrial dysfunction in experimental model of polycystic ovarian syndrome by modulating GPCR41/43 and PROKR1 GPCRs in Neuroscience Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease GPCRs in Oncology and Immunology Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis TIPE proteins control directed migration of human T cells by directing GPCR and lipid second messenger signaling Methods & Updates in GPCR Research An image-based abplex method for high-throughput gpcrs antibody discovery Reviews, GPCRs, and more Current strategic trends in drug discovery: the present as prologue Industry News Exscientia Business Update for Third Quarter 2023 Addex CEO Tim Dyer to Discuss Allosteric Modulators in Neurological Disorders at Jefferies Healthcare Conference in London Sosei Heptares and Kallyope Nominate First GPCR Target for Therapeutic Development in Gastrointestinal Diseases Sosei Heptares Operational Highlights and Consolidated Results for the Third Quarter and First Nine Months of 2023 InterAx Biotech Announces Being the Recipient of a Highly Competitive European Grant to Fund Drug Development and Reports Financing Highlights Neurocrine Biosciences Provides Development Pipeline Update Crinetics Pharmaceuticals Announces November 2023 Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) GPCR signaling contributes to immune characteristics of the microenvironment and the process of EBV-induced lymphomagenesis Tanso Biosciences: Core Technology for Our GPCR Functional Assay Patented in Japan GPCR Events, Meetings, and Webinars November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting NEW January 16 - 19, 2024 | 23rd Annual PEP Talk February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition NEW March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference NEW April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 5 - 10, 2024 | AACR Annual Meeting NEW April 22 - 23, 2024 | Endocrine Metabolic GPCRs May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines NEW October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry NEW July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Post-Doc Research Associate NEW Postdoctoral Fellow Research Scientist/Postdoctoral Associate in Computational Chemistry/Biophysics Post-Doctoral Associate Team Leader Antibody Discovery Staff Scientist (AC-TAP) in Database Development at Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences Octant Apprentice Explore Dr. GPCR Ecosystem

Good day, GPCR folks! Take advantage of our GPCR highlights of the week. Dr. Hannes Schihada and his lab team developed fluorescent analogues for real-time binding studies of orphan GPCR GPR3: Save the dates: November 17: Join our final Dr. GPCR Symposium for the year on GPCRs in Immunology and Oncology! A panel of top experts will discuss in a roundtable starting at 10 AM EST. Find speaker details on the Live Talks page and mark your calendar HERE. You don't want to miss out on our monthly Dr. GPCR Newsletter for exclusive content, check out our latest video featuring Dr. Kathleen Caron. Check out the weekly Classified GPCR News from October 30 to November 4, 2023. GPCR Activation and Signaling The G protein alpha chaperone and guanine-nucleotide exchange factor RIC-8 regulates cilia morphogenesis in Caenorhabditis elegans sensory neurons CaSR links endocytic and secretory pathways via MADD, a Rab11A effector that activates Rab27B Targeting of insulin receptor endocytosis as a treatment to insulin resistance Stepwise phosphorylation of BLT1 defines complex assemblies with β-arrestin serving distinct functions Phosphorylation motif dictates GPCR C-terminal domain conformation and arrestin interaction Ready for the sheet: β-strand folding of phosphorylation clusters guides GPCR binding to arrestin Dietary dibutyryl cAMP supplementation regulates the fat deposition in adipose tissues of finishing pigs via cAMP/PKA pathway GPCR Binders, Drugs, and more Cloning and deorphanization of three inotocin (insect oxytocin/vasopressin-like) receptors and their ligand from the tick Ixodes scapularis Evidence that pyrophosphate acts as an extracellular signalling molecule to exert direct functional effects in primary cultures of osteoblasts and osteoclasts Development of Fluorescent AF64394 Analogues Enables Real-Time Binding Studies for the Orphan Class A GPCR GPR3 Antimalarial and Plasmodium falciparum serpentine receptor 12 targeting effect of FDA approved purinergic receptor antagonist GPCRs in Cardiology, Endocrinology, and Taste Palmitoylation-Dependent Regulation of Cardiomyocyte Rac1 Signaling Activity and Minor Effects on Cardiac Hypertrophy Single cell G-protein coupled receptor profiling of activated kidney fibroblasts expressing transcription factor 21 GPCRs in Neuroscience Pregabalin inhibits purinergic P2Y2 receptor and TRPV4 to suppress astrocyte activation and to relieve neuropathic pain GPCRs in Oncology and Immunology Systems Pharmacodynamic Model of Combination Gemcitabine and Trabectedin in Pancreatic Cancer Cells. Part II: Cell Cycle, DNA Damage Response, and Apoptosis Pathways Spliceosome mutations are associated with clinical response in a phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia Methods & Updates in GPCR Research Mining the ZINC database of natural products for specific, testosterone-like, OXER1 antagonists A 19F-qNMR-Guided Mathematical Model for G Protein-Coupled Receptor Signaling Optical Approaches for Investigating Neuromodulation and G Protein-Coupled Receptor Signaling Protocol for identifying physiologically relevant binding proteins of G-protein-coupled receptors Reviews, GPCRs, and more RGS proteins and cardiovascular Angiotensin II Signaling: Novel opportunities for therapeutic targeting Recent progress in degradation of membrane proteins by PROTACs and alternative targeted protein degradation techniques Ligand selectivity hotspots in serotonin GPCRs Study of G protein-coupled receptors dimerization: From bivalent ligands to drug-like small molecules Structural and Molecular Insights into GPCR Function Hydrophobic interaction between the TM1 and H8 is essential for rhodopsin trafficking to vertebrate photoreceptor outer segments Industry News Sosei Heptares Will Receive US$3.75 Million Payment in Multi-Target Partnership Sosei Heptares Announces Submission of New Drug Application in Japan for Daridorexant (ACT-541468), a Dual Orexin Receptor Antagonist for the Treatment of Insomnia OMass Therapeutics Releases First Protein Structures in PDB, Advances Lupus Therapy Research Structure Therapeutics Receives R&D Achievement of the Year Award for GPCR Research Bryan Roth, Natural Products, and the John Daly Legacy Sosei Heptares’ Partner, Pfizer, Progresses Its GLP-1 Receptor Agonist PF-06954522 into a Phase 1 Trial Andrew Hopkins Inducted into RSC BMCS Hall of Fame and Receives Associated Medal in 2023 'This field is in its infancy': Amgen noncommittal on oral obesity med until phase 1 data arrive Form and Function - Consequences of subcellular cAMP signaling revealed AI Predicts How GPCRs Respond to Drug-Like Molecules Accurately predicting GPCR P2Y1 membrane protein ligand binding with Free Energy Perturbation GPCR Events, Meetings, and Webinars November 10, 2023 | Sosei Heptares Zoom Webinar November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines GPCR Jobs NEW Research Scientist/Postdoctoral Associate in Computational Chemistry/Biophysics NEW Post-Doctoral Associate NEW Team Leader Antibody Discovery Staff Scientist (AC-TAP) in Database Development at Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences Octant Apprentice Head of Human Resource Business Partners Senior Scientist, In vitro pharmacology - Crinetics Pharmaceuticals Senior Director, In vitro pharmacology - Crinetics Pharmaceuticals Explore Dr. GPCR Ecosystem

Hi there GPCR minds! Join us for a deep dive into the world of GPCRs. If you're attending the GPCR Retreat, be sure to swing by our booth and snap a photo at our banner! Plus, don't forget to ask for your special treat. We're proud sponsors and can't wait to connect with all of you. See you there! This week's highlight: Congratulations to the GPCR Therapeutics team for their publication on improving hematopoietic stem cell mobilization using Propranolol. Save the dates: November 17: Join our final Dr. GPCR Symposium for the year on GPCRs in Immunology and Oncology! A panel of top experts will discuss in a roundtable starting at 10 AM EST. Find speaker details on the Live Talks page and mark your calendar HERE. Get the inside scoop by subscribing to our monthly Dr. GPCR Newsletter, and watch our latest video featuring Dr. Kathleen Caron. Check out the weekly Classified GPCR News from October 23rd to 29th, 2023. GPCR Activation and Signaling The GPCR adaptor protein Norbin regulates S1PR1 trafficking and the morphology, cell cycle and survival of PC12 cells GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function GPCR Binders, Drugs, and more GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol Discovery of 3-Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis GPCRs in Cardiology, Endocrinology, and Taste Ageing influences detrusor contractions to prostaglandin, angiotensin, histamine and 5-HT (serotonin), independent to the Rho kinase and extracellular calcium pathways Versatile lactate signaling via HCAR1: a multifaceted GPCR involved in many biological processes GPCRs in Neuroscience Dopaminergic Input Regulates the Sensitivity of Indirect Pathway Striatal Spiny Neurons to Brain-Derived Neurotrophic Factor GPCRs in Oncology and Immunology Comparative Analysis of the GNAI Family Genes in Glioblastoma through Transcriptomics and Single-Cell Technologies Methods & Updates in GPCR Research ThermoBRET: A Ligand-Engagement Nanoscale Thermostability Assay Applied to GPCRs Reviews, GPCRs, and more Illuminating the druggable genome: Pathways to progress Industry News Anatole Klepatsky, Orion's COO, Shared Innovative Insights at LSBC Central European Life Science Investment Conference GPCR Therapeutics Announces Publication on Improving Hematopoietic Stem Cell Mobilization Using Propranolol with GPC-100 Sosei Heptares to Host R&D Day Highlighting its Innovative R&D and Late-Stage Development Progress Parker Moss to Join Exscientia as EVP, Corporate Development Confo Therapeutics Nominated for 'Deal of the Year (>€500 Million)' Award at European Lifestars Awards GPCR Events, Meetings, and Webinars November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 10, 2023 | Sosei Heptares Zoom Webinar November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines GPCR Jobs NEW Staff Scientist (AC-TAP) in Database Development at Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences NEW Octant Apprentice Head of Human Resource Business Partners Senior Scientist, In vitro pharmacology - Crinetics Pharmaceuticals Senior Director, In vitro pharmacology - Crinetics Pharmaceuticals In vivo Antibody Discovery Research Scientist In Vitro Biologist/Molecular Pharmacologist Explore Dr. GPCR Ecosystem

Exploring the intracellular allosteric site GPCRs represent one of the largest and most vital families of cell surface receptors, playing a pivotal role in cellular signaling. For this reason, GPCRs have been a focus of drug development for decades due to their role in regulating essential physiological processes. Conventional GPCR drug discovery has largely focused on orthosteric sites, but recent breakthroughs in understanding allosteric modulation have opened up new avenues for drug development. Recent advances in structural biology and pharmacology have revealed the existence of allosteric sites within GPCRs' intracellular domains. These sites act as molecular switches that can modulate receptor activity, providing an untapped opportunity for drug discovery. Unlike orthosteric ligands that bind directly to the receptor's active site, allosteric modulators target distinct, often less conserved sites on the receptor. This allows for the fine-tuning of receptor activity, leading to more specific and safer drugs. Allosteric binding sites on the receptor are those topographically distinct from (do not exhibit any overlap with) the orthosteric site (Rosenbaum, Rasmussen et al. 2009). Over the past decade, there has been a notable growth in the discovery of allosteric modulators for GPCRs which possess the capability to modulate and fine-tune the affinity and/or efficacy of orthosteric ligands. While this has the potential to enhance GPCR subtype-selectivity, it also presents a significant challenge when it comes to detecting and confirming allosteric behaviors (Keov, Sexton et al. 2011). Allosteric ligands can be classified as positive allosteric modulators (PAMs), which increase the receptor functional and/or affinity for an orthosteric ligand; and negative allosteric modulators (NAMs), that fully or partially dampen the receptor's functional response to the ligand (Wold, Chen et al. 2019). Alternatively, they can function as neutral allosteric ligands (NALs), binding to a receptor's allosteric site without causing any detectable alterations in the receptor or orthosteric ligand behavior (Lindsley, Emmitte et al. 2016). However, a NAM competes for binding with PAMs and NAMs and thereby blocks the effects of positive and negative allosteric modulators (Rodriguez, Nong et al. 2005). Allosteric modulators targeting GPCRs can display one or more of the following pharmacological characteristics: 1) affinity modulation where the resulting change in conformation can influence the orthosteric binding pocket, potentially altering the rate of association, dissociation, or both, of an orthosteric ligand; 2) efficacy modulation where there are modifications in intracellular responses, consequently affecting intrinsic efficacy of the orthosteric ligand; 3) agonism/inverse agonism, where the allosteric modulator can perturb receptor signaling in a manner that is either positive (agonism) or negative (inverse agonism), regardless of whether an orthosteric ligand is present or absent (May, Leach et al. 2007). Advantages of targeting GPCRs allosteric sites Allosteric sites offer a more nuanced approach to modulating GPCR activity, enabling greater specificity and fewer side effects. Allosteric modulators that do not exhibit agonistic properties remain inactive in the absence of endogenous orthosteric activity, therefore having the potential to maintain the temporal and spatial aspects of natural physiological signaling. The significance of spatio-temporal attributes in signaling is demonstrated in processes like neurotransmission and chemokine signaling, extending to numerous other GPCR-regulated systems such as free fatty acid receptors (FFARs), now regarded as targets for therapeutic intervention for metabolic diseases such as liver disease, obesity and diabetes (Wold and Zhou 2018). Moreover, they have the potential to enhance target selectivity, which can arise from greater sequence variation in allosteric sites among receptor subtypes when compared to the conserved orthosteric region, or from selective cooperativity with a particular subtype while excluding others (Christopoulos 2002). This is particularly important when dealing with receptor subtypes that exhibit significant similarity in their orthosteric binding sites, such as chemokine receptors. On the other hand, selectivity could be achieved by merging both orthosteric and allosteric pharmacophores within a single compound, resulting in a novel category of GPCR ligands referred to as 'bitopic' (Valant, Gregory et al. 2008). A third advantage is that they offer the prospect of reducing the risk of overdose, given that their activity is dependent on the concentration of the orthosteric ligand. In this context, allosteric modulators exhibiting constrained positive or negative cooperativity are characterized by having an upper limit on the extent of their allosteric influence, an attribute that offers a considerable degree of adjustability in terms of pharmacological effects, allowing for the administration of substantial doses of allosteric modulators with a diminished risk of target-related toxicity (Wold, Chen et al. 2019). Biased allosteric mechanisms Allosteric sites can differentially modulate G-protein and β-arrestin coupling, enabling the development of biased agonists and antagonists with distinct therapeutic potential. Allosteric antagonists are compounds that inhibit GPCR activity by binding to intracellular allosteric sites. G-protein-biased allosteric antagonists are under investigation for several GPCRs, including CCR2, CCR7, CCR9, CXCR2, and β2AR. Interestingly, although having different chemical structures they exhibit strikingly similar binding positions on their respective receptors. On the other hand, positive allosteric modulators that target intracellular allosteric sites can enhance β-arrestin-mediated signaling pathways. SBI-553, an allosteric modulator of NTSR1, provides valuable insights into how allosteric modulation can selectively enhance β-arrestin-mediated signaling. Structural studies at high resolution have illuminated the intricate interactions between NTSR1 and GRK2. Allosteric agonists binding to intracellular sites can also promote G-protein signaling. PCO371 is a G-protein-biased allosteric agonist for the adenosine receptor A1, with the promise to improve cardiac contractility. Recent advances in structural biology have allowed researchers to visualize the binding of allosteric agonists like PCO371 to Gs-proteins, further elucidating biased signaling mechanisms. The process of designing and evaluating biased ligands for GPCRs is complex but essential for understanding their diverse signaling pathways. Advances in understanding the structural and mechanistic aspects of biased GPCR signaling are crucial for designing effective drug molecules. Additionally, considering conformational kinetics for coupling preference with downstream signaling components, such as β-arrestin and G-protein transducers, is important. Allosteric modulation is gaining prominence in GPCR therapeutics, with the discovery of an intracellular allosteric site common in class A and class B GPCRs, particularly in chemokine receptors. This site allows for the direct modulation of downstream receptor signaling in an allosteric manner. Biased allosteric modulators can enhance the safety and efficacy of GPCR-targeted therapeutics by selectively targeting specific signaling pathways. Notably, SBI-553 and PCO371 have been identified as BAMs with intracellular allosteric binding sites. These findings provide a comprehensive understanding of GPCR biased signaling induced by intracellular allosteric agonists and establish a strong foundation for developing biased drugs targeting GPCRs. Check the original article at https://pubmed.ncbi.nlm.nih.gov/37852356/ #GPCR #DrGPCR #Ecosystem

Hey there! Are you ready for some exciting news in the GPCR world? This week's highlights: Dr. Bianca Plouffe and their colleagues' research on 'β-arrestin-dependent and -independent endosomal GPCR activation by the V2.' Norton Cheng and Dr. JoAnn Trejo's study 'identifies two deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses.' Dr. Robert J Lefkowitz and team's study 'GPCR signal transduction: β-arrestin activates ERK MAPK.' Dr. Thomas P. Sakmar and his team used 'bioluminescence resonance energy transfer to measure cell-surface expression of membrane proteins.' Save the dates: November 2 - 4: We're sponsoring the GPCR Retreat and would love to meet you there! Submit your logo design by Nov 1st on the Logo Contest page. No registration is required to participate. November 17: Join our last Dr. GPCR Symposium of the year on GPCRs in Immunology and Oncology! We've gathered a panel of top experts for a roundtable discussion starting at 10 a.m. EST. Our confirmed speakers are Dr. Xavier Leroy, Dr. Brian Arey, and Dr. J. Silvio Gutkind. You can find more information about them on the Live Talks page and mark your calendar HERE. Subscribe to Dr. GPCR Newsletter for more insights! Check out the weekly Classified GPCR News from October 16th to 22nd, 2023. GPCR Activation and Signaling β-Arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor An siRNA library screen identifies CYLD and USP34 as deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses State-dependent dynamics of extramembrane domains in the β2 -adrenergic receptor Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin GPCR Binders, Drugs, and more Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery Targeting mGluR group III for the treatment of neurodegenerative diseases GPCRs in Neuroscience Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling Ciliary localization of a light-activated neuronal GPCR shapes behavior Methods & Updates in GPCR Research Advancements in the use of xenopus oocytes for modelling neurological disease for novel drug discovery Application of bioluminescence resonance energy transfer to quantitate cell-surface expression of membrane proteins Structural and Molecular Insights into GPCR Function Molecular property, manipulation, and potential use of Opn5 and its homologs Industry News The Leading GPCR Company in Immuno-Oncology, Domain Therapeutics, Presents Groundbreaking Advancements at ESMO 2023 Novo Nordisk to Buy Hypertension Treatment from KBP Biosciences Exscientia to Present New Preclinical Data for AI-designed LSD1 and MALT1 Inhibitors at ESMO 2023 Restoring the function of a human cell surface protein in yeast cells Trevena Reports Favorable TRV045 Topline Safety and Tolerability Data from Proof-of-Concept Studies Sosei Heptares’ President & CEO Chris Cargill Wins Executive of the Year at the Citeline Pharma Intelligence Awards Japan 2023 BioMap and Sanofi to co-develop AI modules for biotherapeutic drug discovery Novartis Kisqali® NATALEE analysis reinforces consistent reduction in risk of recurrence across key subgroups of patients with early breast cancer GPCR Events, Meetings, and Webinars October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines GPCR Jobs Head of Human Resource Business Partners Senior Scientist, In vitro pharmacology - Crinetics Pharmaceuticals Senior Director, In vitro pharmacology - Crinetics Pharmaceuticals In vivo Antibody Discovery Research Scientist In Vitro Biologist/Molecular Pharmacologist Senior Vice President, Oncology Clinical Research Scientist (level I or II) Explore Dr. GPCR Ecosystem

Hi, everyone! Read about the newest discoveries in GPCR research 🙌 Save the dates: November 2 - 4: We're sponsoring the GPCR Retreat and would love to meet you there! Submit a logo design by Nov 1st on the Logo Contest page. No registration is needed to submit your logo design. Subscribe to Dr. GPCR Newsletter to receive more insights! Now check out the weekly Classified GPCR News from October 9th to 15th, 2023. Adhesion GPCRs Piconewton Forces Mediate GAIN Domain Dissociation of the Latrophilin-3 Adhesion GPCR Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs GPCR Activation and Signaling Diuretic hormone 31 activates two G protein-coupled receptors with differential second messengers for diuresis in Drosophila suzukii Beyond the G protein α subunit: investigating the functional impact of other components of the Gαi3 heterotrimers Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand Modes of Action A non-pheromone GPCR is essential for meiosis and ascosporogenesis in the wheat scab fungus GPCR Binders, Drugs, and more Development of Photoswitchable Tethered Ligands that Target the µ-Opioid Receptor Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment GPCRs in Neuroscience The Drosophila blood-brain barrier regulates sleep via Moody G protein-coupled receptor signaling GPCRs in Oncology and Immunology Observational Study of Repeat Immunoadsorption (RIA) in Post-COVID ME/CFS Patients with Elevated ß2-Adrenergic Receptor Autoantibodies-An Interim Report GPR37 expression as a prognostic marker in gliomas: a bioinformatics-based analysis Reviews, GPCRs, and more Parallel evolution of the G protein-coupled receptor GrlG and the loss of fruiting body formation in the social amoeba Dictyostelium discoideum evolved under low relatedness Industry News Nobel Laureates Highlight Symposium Celebrating Lefkowitz’s 50 Years at Duke Novo Nordisk stops Ozempic kidney trial after early signs of success Sosei and PharmEnable extend neurological disease drugs hunt Sosei Heptares’ President & CEO Chris Cargill Wins Executive of the Year at the Citeline Pharma Intelligence Awards Japan 2023 Salipro Biotech and Icosagen Launch Antibody Discovery Collaboration Cryo-EM in Drug Discovery GPCR Events, Meetings, and Webinars NEW October 19, 2023 | ERNEST ECI Zoominar October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Head of Human Resource Business Partners Senior Scientist, In vitro pharmacology - Crinetics Pharmaceuticals Senior Director, In vitro pharmacology - Crinetics Pharmaceuticals In vivo Antibody Discovery Research Scientist In Vitro Biologist/Molecular Pharmacologist Senior Vice President, Oncology Clinical Research Scientist (level I or II) Research Fellow Research Technician II - Surgery Explore Dr. GPCR Ecosystem

Hello GPCR people! Check out our GPCR roundup now, and be the first to read! This week's highlight: Congrats to our partner GPCR Therapeutics, on their expansion into fibrosis with their new research. Save the dates: November 2 - 4: We're sponsoring the GPCR Retreat and would love to meet you there! Join the waitlist by emailing gpcrretreat@uottawa.ca. Submit a logo design by Nov 1st on the Logo Contest page. No registration is needed to submit your logo design. Subscribe now to Dr. GPCR Newsletter to get more info! Check out the weekly Classified GPCR News from October 2nd to 8th, 2023. GPCR Binders, Drugs, and more In silico identification of a biarylamine acting as agonist at human β3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism Development, synthesis and evaluation of novel fluorescent Endothelin-B receptor probes GPCRs in Cardiology, Endocrinology, and Taste GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals GPCRs in Neuroscience Involvement of a silkworm D2-like dopamine receptor in the promotion of feeding and related behaviors Methods & Updates in GPCR Research Functional GPCR expression in eukaryotic LEXSY system Structural and Molecular Insights into GPCR Function Interplay of Cholesterol and Actin in Neurotransmitter GPCR Signaling: Insights from Chronic Cholesterol Depletion Using Statin Side-Chain Dynamics of the α1B -Adrenergic Receptor determined by NMR via Methyl Relaxation Structural determinants of sphingosine-1-phosphate receptor selectivity Industry News Sosei Heptares and Verily Nominate First G-protein-coupled receptor Target for Therapeutic Development DKK 25 million to development of databases supporting medical research ‘Define your own success’: Duke leaders talk success, failure at symposium honoring Nobel Laureate Robert Lefkowitz Integral Molecular Secures Nearly $900K in NIH Funding to Discover Antibodies Against Difficult and Conserved Protein Targets GPCR Therapeutics Expands Pipeline into Fibrosis with a Combination Approach Targeting LPA1 GPCR Events, Meetings, and Webinars October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Senior Scientist, In vitro pharmacology - Crinetics Pharmaceuticals NEW Senior Director, In vitro pharmacology - Crinetics Pharmaceuticals In vivo Antibody Discovery Research Scientist In Vitro Biologist/Molecular Pharmacologist Senior Vice President, Oncology Clinical Research Scientist (level I or II) Research Fellow Research Technician II - Surgery Post-Doc Research Associate Research Technician Explore Dr. GPCR Ecosystem

Hello GPCR enthusiasts! Join us for our weekly GPCR round-up. This week's highlights: Drs. Michel Bouvier, J Silvio Gutkind, and team found that Gαs is essential for GRK selectivity and gene regulation by β2-adrenergic receptor. Dr. Matthew Eddy and lab research on GPCR signaling mechanisms using NMR spectroscopy with labeled receptors. Save the dates: November 2 - 4: We are excited to announce that we are sponsors of the GPCR Retreat and would love to meet you there! Unfortunately, registration has closed, but you can still join the waitlist by emailing gpcrretreat@uottawa.ca. In addition, we are currently seeking a new logo for this renowned event. You can submit your logo design by November 1st, and registration is unnecessary to participate. You can find all the necessary information on the Logo Contest page. Did you know that as a premium member, you enjoy exclusive access to recorded talks from our Dr. GPCR Symposia? Also, If you attended any of the talks, we'd truly value your feedback through our survey. Subscribe now to gain access to exclusive insights from Dr. GPCR Newsletter! And now, without further ado, dive into the latest Classified GPCR News from September 25th to October 1st, 2023. GPCR Activation and Signaling The non-nutritive sweetener sucralose increases β-arrestin signaling at the constitutively active orphan G protein-coupled receptor GPR52 β-Arrestin-independent endosomal cAMP signaling by a polypeptide hormone GPCR Gαs is dispensable for β-arrestin coupling but dictates GRK selectivity and is predominant for gene expression regulation by β2-adrenergic receptor Allosteric modulation of the fish taste receptor type 1 (T1R) family by the extracellular chloride ion Illuminating GPCR signaling mechanisms by NMR spectroscopy with stable-isotope labeled receptors GPCR Binders, Drugs, and more Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2 Antipsychotic displays dual GPCR binding mode GPCRs in Cardiology, Endocrinology, and Taste An extracellular glucose sensor for substrate-dependent secretion and display of cellulose-degrading enzymes Functional Water Channels Within the TSH Receptor - a new paradigm for TSH action with disease implications GPCRs in Oncology and Immunology LPA1-mediated inhibition of CXCR4 attenuates CXCL12-induced signaling and cell migration Respiratory infections predominate after day 100 following B-cell maturation antigen-directed CAR T-cell therapy SSTR2 positively associates with EGFR and predicts poor prognosis in nasopharyngeal carcinoma Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency G protein-coupled receptors: A target for microbial metabolites and a mechanistic link to microbiome-immune-brain interactions Methods & Updates in GPCR Research Polyphosphate uses mTOR, pyrophosphate, and Rho GTPase components to potentiate bacterial survival in Dictyostelium Reviews, GPCRs, and more Network pharmacology -based study on the mechanism of traditional Chinese medicine in the treatment of glioblastoma multiforme Industry News Structure Therapeutics Announces Positive Results from Phase 1b Clinical Study of Oral GLP-1 Receptor Agonist GSBR-1290 and Provides Program Update Septerna sells GPCR program to Vertex for $48 million Merck KGgA collaborates with Exscientia plc in deal worth up to $674M 2023 Half-Year Financial Results and Exciting Developments at Aelis Farma Ion Channel Drug Developer Maxion Therapeutics Appoints Eva-Lotta Allan as Chair of its Board of Directors Novo Nordisk and Evotec collaborate to launch LAB eN², a translational drug discovery accelerator, to address innovation gap in cardiometabolic diseases GPCR Events, Meetings, and Webinars October 2 - 3, 2023 | Celebrating Robert J. Lefkowitz's Career at Duke October 3, 2023, | FREE Seminar: Changing paradigm on Therapeutics targeting Membrane Proteins: from antigen production to candidate validation October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW In vivo Antibody Discovery Research Scientist NEW In Vitro Biologist/Molecular Pharmacologist Senior Vice President, Oncology Clinical Research Scientist (level I or II) Research Fellow Research Technician II - Surgery Post-Doc Research Associate Research Technician Explore Dr. GPCR Ecosystem

Hi readers! Take a few minutes and dive into our GPCR coverage! Our recent Dr. GPCR Symposium about 'GPCRs as Therapeutic Modalities' rocked it! A huge thank you to our amazing speakers and everyone who showed up. If you couldn't make it, no sweat – our premium members can always go back and watch the recorded talks at any time here. For attendees, kindly spare a moment to complete our survey. Save the dates: November 2 - 4: We're proud sponsors of the GPCR Retreat and can't wait to meet you there! Registration is now closed, but you can join the waitlist by emailing gpcrretreat@uottawa.ca. If you're already registered, kindly use the provided form to submit your poster abstracts. Short talk selections will be announced soon. Abstract submissions close on October 2nd. We are also looking for a new logo for this iconic event. Submit your logo design by November 1st. You don't need to be registered to participate. All information is available on the Logo Contest page. Access exclusive insights by subscribing to the Dr. GPCR Newsletter! Dive into the Classified GPCR News from September 18th to 24th, 2023. GPCR Activation and Signaling Rules and mechanisms governing G protein coupling selectivity of GPCRs Location-biased activation of the proton-sensor GPR65 is uncoupled from receptor trafficking GPCR Binders, Drugs, and more An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism GPCRs in Cardiology, Endocrinology, and Taste Structural and functional analysis of salivary intercalated duct cells reveals a secretory phenotype Mesenchymal stromal cell secretory molecules improve the functional survival of human islets AT2 receptor agonist LP2 restores respiratory function in a rat model of bleomycin-induced lung remodelling GPCRs in Neuroscience Photoactivatable Agonist-Antagonist Pair as a Tool for Precise Spatiotemporal Control of Serotonin Receptor 2C Signaling GPCRs in Oncology and Immunology CaaX-motif-adjacent residues influence G protein gamma (Gγ) prenylation under suboptimal conditions Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody Activation of PI3K/Akt pathway by G protein-coupled receptor 37 promotes resistance to cisplatin-induced apoptosis in non-small cell lung cancer Methods & Updates in GPCR Research Target immobilization on glass microfiber membranes as a label-free strategy for hit identification Reviews, GPCRs, and more The discovery, structure, and function of 5-HTR1E serotonin receptor Structural and Molecular Insights into GPCR Function Cryo-EM structures of human GPR34 enable the identification of selective antagonists Industry News Inside the FDA's Form 483 findings at Novo Nordisk's North Carolina semaglutide plant Excellerate Bioscience Announces Site Relocation AI can help to speed up drug discovery — but only if we give it the right data Inversago Pharma divulges new cannabinoid CB1 receptor antagonists BenevolentAI, Exscientia on the comeback trail after securing separate AI drug discovery deals with Merck KGaA Pfizer’s Vydura recommended by NICE for acute migraines Addex mGlu2 NAM Cognition Program Receives €4 Million Grant Confo Therapeutics Appoints Stephen Dowd As Chief Business Officer Call for GPCR Papers opnMe GPCR Route 66+ project. Deadline September 27, 2023 GPCR Events, Meetings, and Webinars October 2 - 3, 2023 | Celebrating Robert J. Lefkowitz's Career at Duke October 3, 2023, | FREE Seminar: Changing paradigm on Therapeutics targeting Membrane Proteins: from antigen production to candidate validation October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Senior Vice President, Oncology Clinical Research NEW Scientist (level I or II) NEW Research Fellow Research Technician II - Surgery Post-Doc Research Associate Research Technician Senior Research Associate, In Vitro Pharmacology - Crinetics Pharmaceuticals Postdoc In Cell Biology Of Protein Trafficking Postdoctoral Fellow Explore Dr. GPCR Ecosystem

Nanobodies (Nbs), known as variable antigen-binding (VHH) domain or single-domain antibodies, are small antigen-binding fragments. Nbs typically consist of a single polypeptide chain which contains the antigen-binding site and the effector functions. They are derived from the heavy-chain antibodies found in camelids (such as camels and llamas) and their small size, about one-tenth the size of conventional antibodies, makes them highly versatile and easy to manipulate for various applications1,2. Nbs are useful tools for dynamic biological systems; they have been used to crystallize flexible membrane proteins, transient multiprotein assemblies, and individual molecules of complex proteins. They have also been used as biosensors to monitor conformational changes of GPCRs in living cells. All the above lightly represent the potential applications of Nbs to facilitate the development of more selective drugs capable of modulating specific signaling pathways, improving therapeutic activity, and minimizing side effects1,2. Some important characteristics of Nbs are: Small size and solubility: Their small size and soluble nature make them ideal building blocks for generating multivalent or multispecific constructs. Tailorable half-life: Nanobodies can extend their half-life through PEGylation or fusion to serum albumin. This allows for tailoring the half-life of nanobodies to increase their therapeutic window depending on the clinical indication. Binding to cryptic epitopes and conformational selection: Nanobodies have a unique shape that allows them to bind to cavities or clefts on the surfaces of proteins that are inaccessible to conventional antibodies. They can recognize cryptic epitopes often composed of discontinuous amino acid segments and occur only within the fully native protein. Nbs can stabilize specific conformations of proteins, including unstable structural intermediates and substates of conformationally complex proteins. Generation, selection and functional expression: Nanobodies can be obtained by immunizing a camelid and cloning the variable VHH gene repertoire. Combinatorial biology methods such as phage display, yeast display, and ribosome display can be used to select nanobodies with desired functions. Most Nbs can be functionally expressed as genetically encoded intrabodies within a eukaryotic cell. This allows for correlating structural or dynamic features observed in vitro with functional observations from living cells. Potential for protein crystallization: Nanobodies can be used to stabilize the protomers of larger protein assemblies and increase the total amount of structured polypeptide. This provides a better starting point for the crystallization of intrinsically unfolded proteins. Some Nbs that have been use for GPCR research are: Nb80: This nanobody stabilized an active-state conformation of the β2 adrenergic receptor (β2AR)3. Nb6B9: This is an affinity-matured nanobody derived from Nb80. It has slower dissociation kinetics at the β2AR and was used to capture the structure of β2AR bound to adrenaline3. Nb35: This nanobody selectively binds to the β2AR·Gs complex and prevents the dissociation of the nucleotide-free complex by the nonhydrolyzable GTP analog GTPγS4. Nb37: Similar to Nb35, this nanobody selectively binds to the β2AR·Gs complex and helps reveal the conformational flexibility of the Gαs α-helical domain. Nb9-8: This nanobody was identified for the M2 muscarinic receptor (M2R) and increased the affinity of agonists. Nb39: This nanobody was identified for the μ-opioid receptor (μOR) and also increased the affinity of agonists4. Nb7: This nanobody improves the diffraction quality of the constitutively active GPCR US28·CX3CL1 complex5. This year Arum Wu et al. reported a library of Nbs to study the allosteric modulation of the rhodopsin receptor activation and investigate the role of specific regions in the switching between different conformational states. This Nbs binds to the extracellular surface of the Rhodopsin receptor and stabilizes the photo-activated receptor in a ground-state-like. The findings of this study showed that the Nb2 binding to native rhodopsin stabilizes its conformation, protects the Schiff base, and prevents protein degradation, potentially offering therapeutic benefits for retinal diseases6. To know more about this report check this link. References: Jin, B. K., Odongo, S., Radwanska, M., & Magez, S. (2023). Nanobodies: A Review of Generation, Diagnostics and Therapeutics. International journal of molecular sciences, 24(6), 5994. https://doi.org/10.3390/ijms24065994 Manglik, A., Kobilka, B. K., & Steyaert, J. (2017). Nanobodies to Study G Protein-Coupled Receptor Structure and Function. Annual review of pharmacology and toxicology, 57, 19–37. https://doi.org/10.1146/annurev-pharmtox-010716-104710 Rasmussen, S. G., Choi, H. J., Fung, J. J., Pardon, E., Casarosa, P., Chae, P. S., Devree, B. T., Rosenbaum, D. M., Thian, F. S., Kobilka, T. S., Schnapp, A., Konetzki, I., Sunahara, R. K., Gellman, S. H., Pautsch, A., Steyaert, J., Weis, W. I., & Kobilka, B. K. (2011). Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature, 469(7329), 175–180. https://doi.org/10.1038/nature09648 Kruse, A. C., Ring, A. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. M., Christopoulos, A., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C., Wess, J., & Kobilka, B. K. (2013). Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature, 504(7478), 101–106. https://doi.org/10.1038/nature12735 Burg, J. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H. L., & Garcia, K. C. (2015). Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science (New York, N.Y.), 347(6226), 1113–1117. https://doi.org/10.1126/science.aaa5026 Wu, A., Salom, D., Hong, J. D., Tworak, A., Watanabe, K., Pardon, E., Steyaert, J., Kandori, H., Katayama, K., Kiser, P. D., & Palczewski, K. (2023). Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain. Nature communications, 14(1), 5209. https://doi.org/10.1038/s41467-023-40911-9

Hello GPCR people! Check out our GPCR roundup now, and be the first to read! This week's highlights: Celebrating Dr. Robert Lefkowitz on his 50 years at Duke. Congratulations. Dr. Graeme Milligan and their colleagues research on Pro-phagocytic function and structural basis of GPR84 signaling. Congrats to Dr. Kevin Wright on his new position as Director of Targeted and Immuno-oncology at GPCR Therapeutics, our partner. Mark your calendars for the following events: September 22- TOMORROW: Attend this Friday's Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities' with Richa Tyagi, Dr. Terry Kenakin, Dr. Oliver Hartley, Dr. Pierre Eftekhari, Dr. Lauren Slosky, Dr. Christel Menet, Dr. Ben Myers and Dr. Niña Caculitan. Since you are reading this newsletter, you only have to click on the event page to join us. November 2 - 4: We are sponsoring the GPCR Retreat and look forward to seeing you there! Registrations are closed but you can send an email to gpcrretreat@uottawa.ca to be added to the waitlist. If you have registered, please submit poster abstracts through this form and the short talk selections will be made. Abstract submissions close on October 2nd. Subscribe to the Dr. GPCR Newsletter and receive valuable insights! Please take a look at the weekly Classified GPCR News from September 11th to 17th, 2023. GPCR Activation and Signaling Characterization of the real-time internalization of nine GPCRs reveals distinct dependence on arrestins and G proteins GPCR Binders, Drugs, and more Studying allosteric regulation of chemokines and antagonists using a nanoscale hCCR3 receptor sensor GPCRs in Oncology and Immunology Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML miR-19a may function as a biomarker of oral squamous cell carcinoma (OSCC) by regulating the signaling pathway of miR-19a/GRK6/GPCRs/PKC in a Chinese population Identification of S1PR4 as an immune modulator for favorable prognosis in HNSCC through machine learning Prediction of survival and immunotherapy response by the combined classifier of G protein-coupled receptors and tumor microenvironment in melanoma Methods & Updates in GPCR Research Genetic atlas of hygro-and thermosensory cells in the vinegar fly Drosophila melanogaster Structural and Molecular Insights into GPCR Function Pro-phagocytic function and structural basis of GPR84 signaling Structural diversity of leukotriene G-protein coupled receptors Industry News Duke University Celebrates Nobel Prize Winner Robert Lefkowitz’s 50 Years of Scientific Discovery Novo Nordisk Foundation Grants Fuel Exciting GPCR and Signaling Protein Research Tools First-In-Class Drug Shows Potential for Treatment of Cannabis Use Disorder Reproducibility of Tanso Biosciences' GPCR Assay Septerna: making another run on GPCRs Addex Mglu2 Nam Cognition Program Receives €4 Million Grant Dr. Kevin Wright Joins GPCR Therapeutics as Director of Targeted and Immuno-oncology Sosei Heptares Adds World-leading Expertise to its Scientific Advisory Board Call for GPCR Papers opnMe GPCR Route 66+ project. Deadline September 27, 2023 GPCR Events, Meetings, and Webinars September 25 - 28, 2023 | Discovery On Target September 27 - 28, 2023 | Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT NEW October 2 - 3, 2023 | Celebrating Robert J. Lefkowitz's Career at Duke October 3, 2023, | FREE Seminar: Changing paradigm on Therapeutics targeting Membrane Proteins: from antigen production to candidate validation October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat- Registration Closed November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Research Technician II - Surgery NEW Post-Doc Research Associate NEW Research Technician Senior Research Associate, In Vitro Pharmacology - Crinetics Pharmaceuticals Postdoc In Cell Biology Of Protein Trafficking Postdoctoral Fellow Researcher / Senior Researcher in Structural Biology Research Specialist Explore Dr. GPCR Ecosystem

Good day readers! Welcome to our latest GPCR updates. This week's highlights: Dr. Yamina Berchiche, Founder and Director of Dr. GPCR, was featured as Superluminal Medicines Launches to Drug Protein Conformations in a Flash. Our partner, Domain Therapeutics, will attend the SACHS 23rd annual biotech event in Europe. Dr. Gregory Tall and team's study on GPR114/ADGRG5, activated by tethered-peptide-agonist, a cleaved adhesion GPCR. Dr. Christopher Langmead and colleagues' work on the 5-HT2C receptor as a therapeutic target for substance use disorders. Save these dates: September 22: Join us for the Dr. GPCR Symposium on ''GPCRs as Therapeutic Modalities' Share your project with a 1-minute abstract video with this form. November 2 - 4: The GPCR Retreat is approaching and we are thrilled to be sponsors! Submit poster abstracts here; short talks will be selected from Abstracts. Abstract submissions close on October 2, and final registration ends on September 21. Subscribe to the Dr. GPCR Newsletter for more insights! Now, explore the Classified GPCR News from September 4th to 10th, 2023. Adhesion GPCRs GPR114/ADGRG5 is activated by its tethered-peptide-agonist because it is a cleaved adhesion GPCR Latrophilin, an adhesion GPCR with galactose-binding lectin domain involved in the innate immune response of Tribolium castaneum GPCR Activation and Signaling Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation GPCR Binders, Drugs, and more Saturated Cannabinoids: Update on Synthesis Strategies and Biological Studies of These Emerging Cannabinoid Analogs GPCRs in Neuroscience Serotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages GPCRs in Oncology and Immunology [1,2,4]Triazolo[1,5-c]pyrimidines as Tools to Investigate A3 Adenosine Receptors in Cancer Cell Lines Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors Methods & Updates in GPCR Research Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats Reviews, GPCRs, and more Understanding class B GPCR agonist binding Structural and Molecular Insights into GPCR Function Structure and Molecular Mechanism of Signaling for the Glucagon-like Peptide-1 Receptor Bound to Gs Protein and Exendin-P5 Biased Agonist Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders Industry News Crinetics’ Once-Daily Oral Paltusotine Achieved The Primary And All Secondary Endpoints In The Phase 3 Pathfndr-1 Study Evaluating Treatment Of Patients With Acromegaly Crinetics Announces September 2023 Inducement Grants Click Therapeutics teams up with addiction treatment maker Indivior to make digital therapeutics for substance use disorders Superluminal Medicines Launches to Drug Protein Conformations in a Flash Andrew Hopkins, Exscientia's CEO, Recognized in TIME Magazine's for Pioneering AI-Driven Drug Discovery Domain Therapeutics CEO Pascal Neuville to Discuss Game-Changing GPCR-Targeting Immunotherapies at Sachs Associates' Biotech Forum Celtarys Research and G-CLIPS join forces to revolutionize transmembrane proteins characterization in drug discovery Confo Therapeutics Appoints Stephen Dowd As Chief Business Officer Septerna Announces Novel GPCR-targeted Program Acquired by Vertex Call for GPCR Papers opnMe GPCR Route 66+ project. Deadline September 27, 2023 GPCR Events, Meetings, and Webinars NEW September 21, 2023 | Breaking Through the Barriers: Unlocking the Future of Ion Channel Drug Discovery with Cryo-EM September 25 - 28, 2023 | Discovery On Target September 27 - 28, 2023 | Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT October 3, 2023 | FREE Seminar: Changing paradigm on Therapeutics targeting Membrane Proteins: from antigen production to candidate validation October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs NEW Senior Research Associate, In Vitro Pharmacology - Crinetics Pharmaceuticals NEW Postdoc In Cell Biology Of Protein Trafficking NEW Postdoctoral Fellow Researcher / Senior Researcher in Structural Biology Research Specialist Science Research Writer Postdoctoral Fellow Research Laboratory Specialist Associate Explore Dr. GPCR Ecosystem

Hello, hello! Stay informed with our GPCR roundup. Mark your calendars for these important events: September 22: Save the date for the Dr. GPCR Symposium on 'GPCRs as Therapeutic Modalities' Showcase your project with a 1-minute abstract video using this form. Our poster session is now an engaging Kumospace discussion. November 2 - 4: Get ready for the upcoming GPCR Retreat! We are excited to share that we are sponsors of this event. You can submit your poster abstracts using this form and short talks will be selected from abstracts. Please remember that the early-bird registration deadline ends tomorrow, the abstract submissions deadline is October 2nd, and the final registration cutoff is September 21st. Subscribe to Dr. GPCR Newsletter to gain access to further insights! Don’t forget to check out the weekly Classified GPCR News from August 28th to September 3rd, 2023. GPCR Activation and Signaling Cell death signaling in Anopheles gambiae initiated by Bacillus thuringiensis Cry4B toxin involves Na+/K+ ATPase GPCR Promiscuity Reshapes Islet Physiology TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy GPCR Binders, Drugs, and more The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol GPCRs in Cardiology, Endocrinology, and Taste Cholecystokinin-A Signaling Regulates Automaticity of Pacemaker Cardiomyocytes Dopamine Receptor D1 Is Exempt from Transforming Growth Factor β-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts GPCRs in Neuroscience System-wide mapping of peptide-GPCR interactions in C. elegans GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders GPCRs in Oncology and Immunology From outside to inside and back again: the lysophosphatidic acid-CCN axis in signal transduction NPFF stimulates human ovarian cancer cell invasion by upregulating MMP-9 via ERK1/2 signaling CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration Methods & Updates in GPCR Research 3DDPDs: describing protein dynamics for proteochemometric bioactivity prediction. A case for (mutant) G protein-coupled receptors Reviews, GPCRs, and more RGS2 and female common diseases: a guard of women's health β-Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives COVID-19, G protein-coupled receptor, and renin-angiotensin system autoantibodies: Systematic review and meta-analysis Structural and Molecular Insights into GPCR Function Analysis of the Dynamics of the Human Growth Hormone Secretagogue Receptor Reveals Insights into the Energy Landscape of the Molecule Focused classifications and refinements in high-resolution single particle cryo-EM analysis Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6 Industry News Septerna Bolsters Leadership Team as the Company Advances its Multi-Product Pipeline Toward Clinical Studies Confo Therapeutics Appoints Dieter Weinand, Former CEO Of Bayer Pharmaceuticals, As Independent Chairman Addex Adx71149 Phase 2 Epilepsy Study Expected To Readout Data In Q2 2024 Addex Announces Participation In The H.C. Wainwright 25th Annual Global Investment Conference X4 Pharmaceuticals to Participate in the Morgan Stanley 21st Annual Global Healthcare Conference CEO Raymond Stevens to Speak at STAT Future Summit on Obesity Therapeutics Call for GPCR Papers NEW opnMe GPCR Route 66+ project. Deadline September 27, 2023 GPCR Events, Meetings, and Webinars September 25 - 28, 2023 | Discovery On Target September 27 - 28, 2023 | Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling" at the DOT NEW October 3, 2023 | FREE Seminar: Changing paradigm on Therapeutics targeting Membrane Proteins: from antigen production to candidate validation October 25 - 27, 2023 | 3rd Annual Meeting IRN I-GPCRNet November 2 - 4, 2023 | GPCR Retreat November 15 - 17, 2023 | MPGPCR Conference November 20 - 23, 2023 | ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 4, 2024 | Chemotactic Cytokines GPCR Jobs Researcher / Senior Researcher in Structural Biology Research Specialist Science Research Writer Postdoctoral Fellow Research Laboratory Specialist Associate Postdoc Research Associate Director, Regulatory Affairs Research Scientist/Senior Scientist I - Molecular Pharmacology Explore Dr. GPCR Ecosystem

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

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

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

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

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

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

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

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

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

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

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

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

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