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Publication Abstract from PubMed

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.

Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.,Nasrallah C, Cannone G, Briot J, Rottier K, Berizzi AE, Huang CY, Quast RB, Hoh F, Baneres JL, Malhaire F, Berto L, Dumazer A, Font-Ingles J, Gomez-Santacana X, Catena J, Kniazeff J, Goudet C, Llebaria A, Pin JP, Vinothkumar KR, Lebon G Cell Rep. 2021 Aug 31;36(9):109648. doi: 10.1016/j.celrep.2021.109648. PMID:34469715^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.