7FD8

Thermostabilised full length human mGluR5-5M bound with L-quisqualic acid

Summary for 7FD8

• Entry DOI: 10.2210/pdb7fd8/pdb
• Related: 7P2L
• EMDB information: 31536 31537
• Descriptor: Metabotropic glutamate receptor 5, 2-acetamido-2-deoxy-beta-D-glucopyranose, (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID, ... (4 entities in total)
• Functional Keywords: g protein coupled receptors, signal transduction, metabotropic glutamate receptor 5 (grm5), membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 195702.07

Authors

Vinothkumar, K.R.,Cannone, G.,Lebon, G. (deposition date: 2021-07-16, release date: 2021-09-08, Last modification date: 2024-10-30)

Primary citation

Nasrallah, C.,Cannone, G.,Briot, J.,Rottier, K.,Berizzi, A.E.,Huang, C.Y.,Quast, R.B.,Hoh, F.,Baneres, J.L.,Malhaire, F.,Berto, L.,Dumazer, A.,Font-Ingles, J.,Gomez-Santacana, X.,Catena, J.,Kniazeff, J.,Goudet, C.,Llebaria, A.,Pin, J.P.,Vinothkumar, K.R.,Lebon, G.
Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.
Cell Rep, 36:109648-109648, 2021

PubMed Abstract: 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.

PubMed: 34469715
DOI: 10.1016/j.celrep.2021.109648

Experimental method

ELECTRON MICROSCOPY (3.8 Å)