期刊
CELL REPORTS
卷 36, 期 9, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109648
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资金
- ATIP grant from CNRS
- Montpellier University
- Labex EpiGenMed (program Investissements d'avenir) [ANR-10-LABX-12-01]
- Ligue Contre le Cancer
- Ministerio de Ciencia e Innovacion
- Agencia Estatal de Investigacion
- ERDF-FEDER European Fund [CTQ2017-89222-R]
- Catalan government [2017 SGR 1604]
- ANR [ANR-17-CE11-0011, ANR-18-CE11-0004, ANR-17-CE11-0046, ANR-17-CE18-0001, ANR-20-CE11-0019]
- Fondation Recherche Medicale (FRM) [DEQ20170326522]
- Medical Research Council [MC-U105184322]
- SERB, India [RJN-094/2017]
- DBT B-Life grant [DBT/PR12422/MED/31/287/2014]
- Department of Atomic Energy, Government of India, Government of India [RTI4006]
- Fondation Recherche Medicale [ING20121226326]
- Agence Nationale de la Recherche (ANR) [ANR-20-CE11-0019, ANR-17-CE11-0011, ANR-18-CE11-0004, ANR-17-CE18-0001] Funding Source: Agence Nationale de la Recherche (ANR)
mGluRs are dimeric G-protein-coupled receptors activated by L-glutamate, which can be activated by different agonists and allosteric modulators. Agonists induce a large movement between subunits, while PAM stabilizes an active conformation independent of agonist-induced conformational changes.
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(5) 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.
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