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Hey there, curious minds! Want to know what’s buzzing in the world of GPCRs? Join us for this week’s update, where you’ll find all the latest breakthroughs and exciting developments in GPCR research. We can’t wait to share it with you! This Week’s Highlights: Harnessing Deep Mutational Scanning for Enhanced Drug Discovery Cam Sinh Lu GPCR-BSD: a database of binding sites of human G-protein coupled receptors under diverse states Fan Liu , Han Zhou , Xiaonong Li , Liangliang Zhou , Chungong Yu , Haicang Zhang , Dongbo Bu 🤩 Seriously, why would you want to miss out on all the awesomeness that comes with a DrGPCR Premium Membership ? As a premium member , you have access to all the complimentary perks as well as: Dr. GPCR University 🎥 Access to the recorded classes of GPCR Courses and talks from Symposia 💲 Discounted GPCR courses GPCR Forum Initiate a vibrant conversation or seek assistance GPCR Events to keep you informed and engaged GPCR Jobs connecting candidates with positions Direct line to the Dr. GPCR community members Networking is crucial in professional endeavors :) Big Update! Starting in 2025, content access to Classified GPCR News will only be reserved for Premium Members. This strategic decision to limit free content is essential as we need to increase revenue to support the community. Classified GPCR News  Let’s dive into the   Classified GPCR News from November 4th to 10th, 2024 Industry News Lexaria Updates Fast-Moving GLP-1 'Arm's Race' Developments Five protein-design questions that still challenge AI Prix Galien USA: Domain Therapeutics Nominated for the Prestigious Best Startup Award Tectonic Therapeutic Announces Positive Phase 1a Results in AHA 2024 Presentation for TX45, a Long-acting, Fc-Relaxin Fusion Protein Nxera Pharma and Antiverse partner on GPCRs Nxera Pharma’s Partner Centessa Initiates Phase 2 Trial with ORX750, a Novel Orexin Receptor 2 (OX2R) Agonist AI, Synthetic Biology and Drug Discovery- with Aikium's Dr Venkatesh Mysore Trevena teeters in dangerous territory, terminating CEO and other execs amid strategic review Trevena Reports Third Quarter 2024 Results and Provides Business Update GPCR Events, Meetings, and Webinars NEW November 18 - 20, 2024 | 7th CB1 & CB2 Targeting Drug Development Summit November 25 - 26, 2024 | 6th International Conference on Stem Cell, Tissue Engineering and Regenerat November 25 - 27, 2024 | 1st Virtual GPCR Forum Conference November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe December 10 - 12, 2024 | Pharmacology 2024 January 13 - 16, 2025 | PepTalk 2025 January 25 - 29, 2025 | SLAS 2025 February 15 - 16, 2025 | Structural and Functional Approaches in GPCR Drug Discovery February 15 - 19, 2025 | BPS 2025 February 16 - 21, 2025 | Harnessing the Power of Advanced Multimodal Approaches to GPCR Drug Discovery March 12 - 14, 2025 | NextGen Biomed 2025 March 25 - 28, 2025 | 10th German Pharm-Tox Summit April 1 - 5, 2025 | XXIII GEM Meeting in 2025 April 3 - 6, 2025 | ASPET 2025 April 14 - 17, 2025 | 20th Drug Discovery Chemistry April 24 - 27, 2025 | American Physiology Summit 2025 April 25 - 30, 2025 | AACR Annual Meeting 2025 May 12 - 15, 2025 | PEGS 2025 May 20 - 22, 2025 | SLAS Europe 2025 June 16 - 19, 2025 | BIO International Convention 2025 July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Scientist I Cell Biology - Tectonic Therapeutic NEW Senior Principal Scientist, Medicinal Chemistry PhD fellowship in GPCR mechanosensing Senior Scientist, GPCR Pharmacology Research Associate - Professor Graeme Milligan Postdoc in Molecular Pharmacology - The Hauser Group Postdoctoral Scholar – iPSC in cardiac and endothelial cell function Protein Biochemist/Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry GPCR Activation and Signaling Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications Sphingosine-1-phosphate activates LRRC8 volume-regulated anion channels through Gβγ signalling GPCR Binders, Drugs, and more PGE2 Binding Affinity of Hemocyte Membrane Preparations of Manduca sexta and Identification of the Receptor-Associated G Proteins in Two Lepidopteran Species GPCRs in Neuroscience Role of the GRK2/3 N-terminus in discriminating the endocytic effects of opioid agonist drugs GPCRs in Oncology and Immunology GPR56: GPCR as a guardian against ferroptosis Methods & Updates in GPCR Research Memprot.GPCR-ModSim: Modelling and simulation of membrane proteins in a nutshell Ciliary length variations impact cilia-mediated signaling and biological responses Structural and Molecular Insights into GPCR Function GPCR-BSD: a database of binding sites of human G-protein coupled receptors under diverse states Become a Premium Member! 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Deep mutational scanning (DMS) is a powerful method for studying the functional consequences of various genetic variants within a specific gene or genomic region. This technique combines high-throughput DNA sequencing with systematic mutagenesis to create and assess the impact of many different mutations simultaneously (Araya & Fowler, 2011). It has particular relevance in the field of drug discovery, offering transformative potential across various stages of the pipeline, from target identification and validation to lead optimisation. Target Identification and Validation In drug discovery, the identification of robust drug targets is critical. DMS can be used to comprehensively assess the functional impact of mutations in a candidate protein, helping to validate whether drugs can effectively target it. By systematically mutating every amino acid in the protein and assessing the resulting phenotype, researchers can identify essential domains and residues crucial for the protein's biological function. This high-resolution mapping can confirm the protein’s role in disease pathology and highlight allosteric sites that might be more amenable to drug targeting than the active site, providing a solid rationale for prioritising it as a drug target. For example, a DMS approach has been conducted to reveal the functional importance of each residue in proton recognition in GPR68. The result suggested that, in contrast to other proton-sensitive channels and receptors, GPR68 did not have a single essential site for proton recognition. Instead, a collection of titratable residues spans from the extracellular surface to the transmembrane area, linking with canonical class A GPCR activation motifs to initiate proton-sensing GPCRs. Specifically, the study revealed that the protonation of key residues surrounding an extracellular facing cavity resulted in conformational rearrangements with TM3 as a central conduit (Howard et al., 2024).    Lead Optimisation Once potential lead compounds are identified, DMS can be employed to refine these molecules for enhanced potency, efficacy, and specificity. By examining how mutations in the target protein affect its interaction with the drug, researchers can identify which protein regions are crucial for binding the drug and which mutations affect its potency and efficacy. This data can guide the modification of the chemical structure of the lead compounds to improve potency and selectivity, thereby optimising the drug's design. Predicting and Overcoming Drug Resistance A significant challenge in drug development, particularly in the treatment of infectious diseases and cancer, is resistance. Mutations in target proteins can lead to decreased drug affinity and/or potency, rendering treatments ineffective. DMS provides a proactive approach to this problem by predicting potential resistance mutations before they are clinically observed (Pines et al., 2020). Furthermore, understanding these resistance mechanisms enables the design of next-generation drugs that either avoid these mutations or remain effective against them. It also helps in combination therapy strategies, where drugs are designed to target multiple sites or pathways simultaneously, reducing the likelihood of resistance development. Precision Medicine Finally, DMS aids in the advent of precision medicine by enabling a more detailed understanding of how genetic variation within human populations affects drug response. By evaluating a broad spectrum of mutations, DMS can help predict which patient subpopulations will respond to a drug and which might suffer adverse effects. This can guide the development of more personalised therapies tailored to the genetic makeup of individual patients, enhancing therapeutic outcomes and minimising harm. Limitations Deep mutational scanning encounters several constraints that affect its broad applicability and the interpretation of its results. The choice of model systems, such as yeast, bacteria, or mammalian cells, can heavily influence the method's effectiveness. Certain systems might not replicate the natural environment or post-translational modifications observed in humans, potentially leading to inconsistencies in how mutations influence protein function in real-world scenarios. Moreover, DMS requires considerable resources, including time, financial investment, and specialised expertise, limiting accessibility for some research laboratories. Additionally, DMS is not universally applicable to all proteins; it struggles with proteins that lack a clear function or perform multiple complex roles. Finally, current sequencing technology restricts the mutagenizable region to about 300 amino acids, although this limitation has eased from an initial 25 amino acids and is expected to further diminish as sequencing technology advances (Fowler et al., 2014). Future directions As deep mutational scanning continues to evolve, its future directions will likely focus on enhancing its scalability, accuracy, and applicability across broader biological contexts. An essential advancement will be the integration of DMS with emerging sequencing technologies that allow for longer reads and more accurate mapping of complex mutations. This could expand the method's capability to explore larger genomic regions and more intricate genetic variations. Additionally, combining DMS with computational modelling and machine learning algorithms promises to improve the predictive power of the technique, enabling more precise interpretations of how mutations affect protein function in diverse cellular environments. Another promising development is the application of DMS to a wider array of biological systems, including multicellular organisms and human cells, to better mimic physiological conditions and disease states. This would help bridge the gap between in-vitro findings and clinical outcomes. In conclusion, deep mutational scanning is a versatile tool in drug discovery, providing detailed insights that can drive the early stages of target and lead identification, combat drug resistance, and refine therapeutic indices to produce safer and more effective drugs. Reference Araya, C. L., & Fowler, D. M. (2011). Deep mutational scanning: assessing protein function on a massive scale. Trends in Biotechnology , 29 (9), 435–442. https://doi.org/10.1016/j.tibtech.2011.04.003 Fowler, D. M., Stephany, J. J., & Fields, S. (2014). Measuring the activity of protein variants on a large scale using deep mutational scanning. Nature Protocols , 9 (9), 2267–2284. https://doi.org/10.1038/nprot.2014.153 Howard, M. K., Hoppe, N., Huang, X.-P., Macdonald, C. B., Mehrotra, E., Patrick Rockefeller Grimes, Zahm, A. M., Trinidad, D. D., English, J. G., Coyote-Maestas, W., & Aashish Manglik. (2024). Molecular basis of proton-sensing by G protein-coupled receptors. BioRxiv (Cold Spring Harbor Laboratory) . https://doi.org/10.1101/2024.04.17.590000 Pines, G., Fankhauser, R. G., & Eckert, C. A. (2020). Predicting Drug Resistance Using Deep Mutational Scanning. Molecules , 25 (9), 2265. https://doi.org/10.3390/molecules25092265

Get your space suits on, GPCR cadets! The GPCR rocket is all fueled and ready to blast off into a galaxy of incredible advancements, now powered up with a series of cosmic GPCR events for the year ahead. It’s time to mark your calendars and save the dates—let’s make some stellar memories together! 🚀✨ This Week’s Highlights: Congrats to: Ya-Tzu Li , our notable contributor, for her superb undergrad paper along with Hao-Jen Hsu , Chun-Chun Chang , et al.   about State transitions of coupled Gi-protein: Insights into internal water channel dynamics within dopamine receptor D3 from in silico submolecular analyses Joseph Crecelius , Adriano Marchese , et al. for their excellent work on Receptor determinants for ß-arrestin functional specificity at C-X-C chemokine receptor 5 (CXCR5) Panjamaporn Sangwung , Alejandra Tomas , Kyle Sloop , et al. for their outstanding study on Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease Milena Malcharek , Graham Ladds , et al. for their extensive research on The role of receptor activity-modifying proteins in obesity and diabetes mellitus Maleesha Ubhayarathna , Christopher Langmead , Gregory Stewart , et al. for their fantastic review on Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders Leigh Walker , Christopher Langmead , Andrew Lawrence , et al. for their remarkable analysis on Targeting muscarinic receptors for the treatment of alcohol use disorders: Opportunities and hurdles for clinical development 👨‍💻 Why would you want to miss out on all the fun with a DrGPCR Premium Membership ? 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Classified GPCR News  Let’s dive into the   Classified GPCR News from October 28th to November 3rd, 2024 Industry News Nxera Pharma Operational Highlights and Consolidated Results for the Third Quarter and First Nine Months of 2024 Nasdaq debutante Septerna swells its IPO to $331m Nxera Pharma and Antiverse Enter Collaboration To Design Novel GPCR- Targeted Antibody Therapeutics Using Generative AI Zombie Fungi Hijack Hosts’ Brains GPCR Therapeutics, Inc. has received Orphan Drug Designation (ODD) from the FDA for its hematopoietic stem cell mobilization agent It’s not just obesity. Drugs like Ozempic will change the world GPCR Events, Meetings, and Webinars November 5 - 7, 2024 | 16th Annual PEGS Europe   NEW November 25 - 26, 2024 | 6th International Conference on Stem Cell, Tissue Engineering and Regenerat November 25 - 27, 2024 | 1st Virtual GPCR Forum Conference November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe NEW December 10 - 12, 2024 | Pharmacology 2024 NEW January 13 - 16, 2025 | PepTalk 2025 NEW January 25 - 29, 2025 | SLAS 2025 NEW February 15 - 16, 2025 | Structural and Functional Approaches in GPCR Drug Discovery NEW February 15 - 19, 2025 | BPS 2025 NEW February 16 - 21, 2025 | Harnessing the Power of Advanced Multimodal Approaches to GPCR Drug Discovery NEW March 12 - 14, 2025 | NextGen Biomed 2025 NEW March 25 - 28, 2025 | 10th German Pharm-Tox Summit NEW April 1 - 5, 2025 | XXIII GEM Meeting in 2025 NEW April 3 - 6, 2025 | ASPET 2025 NEW   April 14 - 17, 2025 | 20th Drug Discovery Chemistry NEW   April 24 - 27, 2025 | American Physiology Summit 2025 NEW April 25 - 30, 2025 | AACR Annual Meeting 2025 NEW May 12 - 15, 2025 | PEGS 2025 NEW May 20 - 22, 2025 | SLAS Europe 2025 NEW June 16 - 19, 2025 | BIO International Convention 2025 July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Scientist I Cell Biology - Tectonic Therapeutic PhD fellowship in GPCR mechanosensing Senior Scientist, GPCR Pharmacology Research Associate - Professor Graeme Milligan Postdoc in Molecular Pharmacology - The Hauser Group Postdoctoral Scholar – iPSC in cardiac and endothelial cell function Protein Biochemist/Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry GPCR Activation and Signaling GPCR signalling: Yet another variant route in a highly complex road map Transactivation of the EGF receptor as a novel desensitization mechanism for G protein-coupled receptors, illustrated by dopamine D2-like and β2 adrenergic receptors Receptor determinants for ß-arrestin functional specificity at C-X-C chemokine receptor 5 (CXCR5) State transitions of coupled Gi-protein: Insights into internal water channel dynamics within dopamine receptor D3 from in silico submolecular analyses GPCRs in Cardiology, Endocrinology, and Taste Adipose tissue in older individuals: a contributing factor to sarcopenia Asprosin regulates male reproduction in teleosts: an in vitro study in Channa punctata GPCRs in Neuroscience Neuron specific quantitation of Gαolf expression and signaling in murine brain tissue Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse GPCRs in Oncology and Immunology The GPCR adaptor protein Norbin controls the trafficking of C5aR1 and CXCR4 in mouse neutrophils Mechanistic exploration of bioactive constituents in Gnetum gnemon for GPCR-related cancer treatment through network pharmacology and molecular docking The Effect of Cancer-Associated Mutations on Ligand Binding and Receptor Function - A Case for the 5-HT2C Receptor Reviews, GPCRs, and more Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors Ligand bias at the muscarinic acetylcholine receptor family: Opportunities and challenges Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease The role of receptor activity-modifying proteins in obesity and diabetes mellitus Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders Targeting muscarinic receptors for the treatment of alcohol use disorders: Opportunities and hurdles for clinical development Chemokine CXCL13-CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases Structural and Molecular Insights into GPCR Function Native mass spectrometry prescreening of G protein-coupled receptor complexes for cryo-EM structure determination Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics Molecular determinants of neuropeptide-mediated activation mechanisms in tachykinin NK1 and NK2 receptors Become a Premium Member! 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< GPCR News < GPCRs in Oncology and Immunology Gallein, G protein βγ subunits inhibitor, suppresses the TGF-α-induced migration of hepatocellular carcinoma cells via inhibition of the c-Jun N-terminal kinase Published date November 13, 2024 Abstract "G protein-coupled receptor (GPCR) signaling regulates a wide range of pathophysiological cell functions via G protein α and βγ subunits. Small molecules targeting the subunits of Gα and Gβγ have been developed as cancer therapeutics. We have previously reported that transforming growth factor-α (TGF-α) induces the migration of human hepatocellular carcinoma (HCC) HuH7 cells through the activation of AKT, p38 mitogen-activated protein kinase (MAPK), Rho-kinase and c-Jun N-terminal kinase (JNK). This study aims to determine whether Gβγ subunits regulate the TGF-α-induced migration of HCC HuH7 cells using gallein, a Gβγ subunits inhibitor. The Janus family of tyrosine kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was also involved in the regulation of the migration. Gallein significantly reduced the TGF-α-induced cell migration. In contrast, fluorescein, a gallein-related compound that has no effect on Gβγ subunits, failed to affect the cell migration. Gallein suppressed the TGF-α-stimulated phosphorylation of JNK without affecting the phosphorylation of epidermal growth factor receptor, AKT, p38 MAPK, target protein of Rho-kinase and STAT3. Conversely, fluorescein did not attenuate the phosphorylation of JNK. These results strongly suggest that Gβγ subunits act as positive regulators in TGF-α-induced migration of HCC cells via the JNK signalling pathway." Authors Rie Matsushima-Nishiwaki, Yoh Honda, Haruhiko Tokuda, Osamu Kozawa Source Contribute to the GPCR News Coming soon Become a Contributor Classified GPCR News Call for GPCR papers GPCR Industry News Adhesion GPCRs GPCR Events, Meetings, and Webinars Reviews, GPCRs, and more GPCR Binders, Drugs, and more Methods & Updates in GPCR Research GPCRs in Neuroscience GPCRs in Cardiology, Endocrinology, and Taste GPCRs in Oncology and Immunology Structural and molecular insights into GPCR function GPCR Activation and Signaling More from Dr. GPCR Create an account and get our contributors articles in your inbox Subscribe to the Dr. GPCR Monthly Newsletter today! Follow the Dr. GPCR News and get weekly notifications about the GPCR field Share < Previous Next >

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