Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.
|Title||Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Nasrallah C, Cannone G, Briot J, Rottier K, Berizzi AE, Huang C-Y, Quast RB, Hoh F, Banères J-L, Malhaire F, Berto L, Dumazer A, Font-Ingles J, Gómez-Santacana X, Catena J, Kniazeff J, Goudet C, Llebaria A, Pin J-P, Vinothkumar KR, Lebon G|
|Date Published||2021 Aug 31|
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 mGlu 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.
|Alternate Journal||Cell Rep|
|PubMed Central ID||PMC8424648|