
@article {152902,
	title = {Conformational diversity in class C GPCR positive allosteric modulation.},
	journal = {Nat Commun},
	volume = {16},
	year = {2025},
	month = {2025 Jan 13},
	pages = {619},
	abstract = {<p>The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state.</p>
},
	keywords = {Allosteric Regulation, Animals, Cryoelectron Microscopy, Glutamic Acid, HEK293 Cells, Humans, Models, Molecular, Protein Binding, Protein Conformation, Protein Domains, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Signal Transduction},
	issn = {2041-1723},
	doi = {10.1038/s41467-024-55439-9},
	author = {Cannone, Giuseppe and Berto, Ludovic and Malhaire, Fanny and Ferguson, Gavin and Fouillen, Aurelien and Balor, St{\'e}phanie and Font-Ingles, Joan and Llebaria, Amadeu and Goudet, Cyril and Kotecha, Abhay and Vinothkumar, Kutti R and Lebon, Guillaume}
}
@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}
}
