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Título: | Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations |
Autor: | Nasrallah, Chady; Cannone, Giuseppe; Briot, Julie; Rottier, Karine; Berizzi, Alice E.; Huang, Chia-Ying; Quast, Robert B.; Hoh, Francois; Banères, Jean-Louis; Malhaire, Fanny; Berto, Ludovic; Dumazer, Anaëlle; Font, Joan CSIC ORCID; Gómez-Santacana, Xavier CSIC ORCID; Catena, Juan Lorenzo CSIC ORCID; Kniazeff, Julie; Goudet, Cyril; Llebaria, Amadeu CSIC ORCID; Pin, Jean Philippe; Vinothkumar, Kutti R.; Lebon, Guillaume | Palabras clave: | G-protein-coupled receptors Signal transduction Glutamate Metabotropic glutamate receptor 5 Allosteric modulators Cryo-EM X-ray crystallography Photochromic ligands |
Fecha de publicación: | 31-ago-2021 | Editor: | Elsevier | Citación: | Cell Reports 36, 9: 109648 (2021) | Resumen: | 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. | Versión del editor: | https://doi.org/10.1016/j.celrep.2021.109648 | URI: | http://hdl.handle.net/10261/251526 | DOI: | 10.1016/j.celrep.2021.109648 |
Aparece en las colecciones: | (IQAC) Artículos |
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1-s2.0-S2211124721010913-main.pdf | Artículo principal | 5,42 MB | Adobe PDF | Visualizar/Abrir |
ScienceDirect_files_04Oct2021_11-18-39.930.zip | Material suplementario | 20,01 MB | Unknown | Visualizar/Abrir |
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