Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

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-t...

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Detalles Bibliográficos
Autores: 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, Gómez-Santacana, Xavier, Catena, Juan Lorenzo, Kniazeff, Julie, Goudet, Cyril, Llebaria, Amadeu, Pin, Jean Philippe, Vinothkumar, Kutti R., Lebon, Guillaume
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/251526
Acceso en línea:http://hdl.handle.net/10261/251526
Access Level:acceso abierto
Palabra clave:G-protein-coupled receptors
Signal transduction
Glutamate
Metabotropic glutamate receptor 5
Allosteric modulators
Cryo-EM
X-ray crystallography
Photochromic ligands
Descripción
Sumario: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.

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