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

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

Edité par CCSD ; Elsevier Inc -

International audience. 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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