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-Structure paper
タイトル | Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations. |
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ジャーナル・号・ページ | Cell Rep, Vol. 36, Issue 9, Page 109648, Year 2021 |
掲載日 | 2021年8月31日 |
著者 | Chady Nasrallah / Giuseppe Cannone / Julie Briot / Karine Rottier / Alice E Berizzi / Chia-Ying Huang / Robert B Quast / Francois Hoh / Jean-Louis Banères / Fanny Malhaire / Ludovic Berto / Anaëlle Dumazer / Joan Font-Ingles / Xavier Gómez-Santacana / Juanlo Catena / Julie Kniazeff / Cyril Goudet / Amadeu Llebaria / Jean-Philippe Pin / Kutti R Vinothkumar / Guillaume Lebon / |
PubMed 要旨 | 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 ...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. |
リンク | Cell Rep / PubMed:34469715 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.54 - 4.0 Å |
構造データ | EMDB-31536, PDB-7fd8: EMDB-31537, PDB-7fd9: PDB-7p2l: |
化合物 | ChemComp-NAG: ChemComp-QUS: ChemComp-Y01: ChemComp-Z99: ChemComp-4YI: ChemComp-HOH: |
由来 |
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キーワード | MEMBRANE PROTEIN / G protein coupled receptors / Signal transduction / Metabotropic glutamate receptor 5 (GRM5) / G-protein coupled receptors / metabotropic glutamate receptor / inactive state / SIGNALING PROTEIN / G protein coupled receptor / mGlu5 7TM / photoswitchable ligand / allosteric modulator |