
@article {99104,
	title = {Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.},
	journal = {Cell Rep},
	volume = {36},
	year = {2021},
	month = {2021 Aug 31},
	pages = {109648},
	abstract = {<p>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.</p>
},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2021.109648},
	author = {Nasrallah, Chady and Cannone, Giuseppe and Briot, Julie and Rottier, Karine and Berizzi, Alice E and Huang, Chia-Ying and Quast, Robert B and Hoh, Francois and Ban{\`e}res, Jean-Louis and Malhaire, Fanny and Berto, Ludovic and Dumazer, Ana{\"e}lle and Font-Ingles, Joan and G{\'o}mez-Santacana, Xavier and Catena, Juanlo and Kniazeff, Julie and Goudet, Cyril and Llebaria, Amadeu and Pin, Jean-Philippe and Vinothkumar, Kutti R and Lebon, Guillaume}
}
