Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations
Chady Nasrallah, Giuseppe Cannone, Julie Briot, Karine Rottier, Alice E. Berizzi, Chia‐Ying Huang, Robert B. Quast, François Hoh, Jean‐Louis Banères, Fanny Malhaire, Ludovic Berto, Anaëlle Dumazer, Joan Font, Xavier Gómez‐Santacana, Juanlo Catena, Julie Kniazeff, Cyril Goudet, Amadeu Llebaria, Jean‐Philippe Pin, Kutti R. Vinothkumar, Guillaume Lebon
Abstract
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.