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

Chady Nasrallah (1) , Giuseppe Cannone (2) , Julie Briot (1) , Karine Rottier (1) , Alice Berizzi (1) , Chia-Ying Huang (3) , Robert Quast (4) , Francois Hoh (4) , Jean-Louis Banères (5) , Fanny Malhaire (1) , Ludovic Berto (1) , Anaëlle Dumazer (1) , Joan Font-Ingles (6) , Xavier Gómez-Santacana (1, 6) , Juanlo Catena (6) , Julie Kniazeff (1) , Cyril Goudet (1) , Amadeu Llebaria (6) , Jean-Philippe Pin (1) , Kutti Vinothkumar (7) , Guillaume Lebon (1)

1 IGF - Institut de Génomique Fonctionnelle
2 LMB - MRC Laboratory of Molecular Biology [Cambridge, UK]
3 PSI - Paul Scherrer Institute
4 CBS - Centre de Biochimie Structurale [Montpellier]
5 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
6 MCS (IQAC-CSIC) - Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia
7 TIFR - Tata Institute for Fundamental Research

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.

Mots clés: signal transduction; photochromic ligands; metabotropic glutamate receptor 5; G-protein-coupled receptors; X-ray crystallography; allosteric modulators; cryo-EM; glutamate

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire; Cristallographie

Chady Nasrallah, Giuseppe Cannone, Julie Briot, Karine Rottier, Alice Berizzi, et al.. Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations. Cell Reports, 2021, 36 (9), pp.109648. ⟨10.1016/j.celrep.2021.109648⟩. ⟨hal-03340751⟩