Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations
| Autor: | François Hoh, Julie Kniazeff, Juan Lorenzo Catena, Cyril Goudet, Jean-Philippe Pin, Xavier Gómez-Santacana, Anaëlle Dumazer, Jean-Louis Banères, Ludovic Berto, Fanny Malhaire, Amadeu Llebaria, Robert B. Quast, Alice E. Berizzi, Giuseppe Cannone, Kutti R. Vinothkumar, Chia-Ying Huang, Chady Nasrallah, Guillaume Lebon, Julie Briot, Joan Font-Ingles, Karine Rottier |
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| Přispěvatelé: | Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Paul Scherrer Institute (PSI), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (MCS (IQAC-CSIC)), Tata Institute for Fundamental Research (TIFR), Ministerio de Ciencia e Innovación (España), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Guerineau, Nathalie C., MRC, Lab Mol Biol, Cambridge, England, Partenaires INRAE, The Swiss Light Source (SLS) (SLS-PSI), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Química Avançada de Catalunya (IQAC), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), National Centre for Biological Sciences [TIFR] (NCBS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Allosteric modulators [SDV]Life Sciences [q-bio] G-protein-coupled receptors Signal transduction Crystallography X-Ray photochromic ligands Excitatory Amino Acid Agonists Receptor Cryo-EM 0303 health sciences Metabotropic glutamate receptor 5 Chemistry Protein Stability 030302 biochemistry & molecular biology metabotropic glutamate receptor 5 Glutamate receptor 3. Good health [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biophysics [SDV] Life Sciences [q-bio] allosteric modulators Glutamate signal transduction Protein Binding Agonist animal structures medicine.drug_class Receptor Metabotropic Glutamate 5 Allosteric regulation glutamate [SDV.BC]Life Sciences [q-bio]/Cellular Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Structure-Activity Relationship medicine [CHIM.CRIS]Chemical Sciences/Cristallography Humans Protein Interaction Domains and Motifs [CHIM.CRIS] Chemical Sciences/Cristallography [SDV.BC] Life Sciences [q-bio]/Cellular Biology 030304 developmental biology G protein-coupled receptor X-ray crystallography Cryoelectron Microscopy Protein Subunits HEK293 Cells Metabotropic glutamate receptor Photochromic ligands Biophysics cryo-EM Excitatory Amino Acid Antagonists |
| Zdroj: | Cell Reports Cell Reports, Elsevier Inc, 2021, 36 (9), pp.109648. ⟨10.1016/j.celrep.2021.109648⟩ Digital.CSIC. Repositorio Institucional del CSIC instname Cell Reports, 2021, 36 (9), pp.109648. ⟨10.1016/j.celrep.2021.109648⟩ |
| ISSN: | 2211-1247 |
| Popis: | Summary Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus flytrap domain is regulated by positive (PAM) or negative (NAM) allosteric modulators binding to the 7-transmembrane domain (7TM). We report the cryo-electron microscopy structures of fully inactive and intermediate-active conformations of mGlu5 receptor bound to an antagonist and a NAM or an agonist and a PAM, respectively, as well as the crystal structure of the 7TM bound to a photoswitchable NAM. The agonist induces a large movement between the subunits, bringing the 7TMs together and stabilizing a 7TM conformation structurally similar to the inactive state. Using functional approaches, we demonstrate that the PAM stabilizes a 7TM active conformation independent of the conformational changes induced by agonists, representing an alternative mode of mGlu activation. These findings provide a structural basis for different mGluR activation modes. Graphical abstract Highlights • Cryo-EM analysis of thermostabilized mGlu5 receptor bound to inhibitors or activators • X-ray structure of trans-Alloswitch-1 bound to thermostable mGlu5 7TMs • Photopharmacology provides insight into allosteric regulation of mGlu5 7TMs • Multiple conformations of mGlu5 receptor activate G protein Nasrallah et al. present cryo-EM structures of thermostabilized mGlu5 dimer bound to inhibitors and activators as well as an X-ray structure of mGlu5 7TM-bound photoswitchable ligand alloswitch-1. The structural and functional analyses reveal different modes of mGLu5 receptor activation and provide a structural basis for mGlu receptor activation mechanism. |
| Databáze: | OpenAIRE |
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