期刊
NATURE
卷 594, 期 7864, 页码 589-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03641-w
关键词
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资金
- Japan Synchrotron Radiation Research Institute [2019A2543, 2019B2543, 2019A2541, 2019B2541]
- mGlu2 NAMs [NAM563, NAM597]
- National Key R&D Program of China [2018YFA0507000]
- National Science Foundation of China [31825010, 31830020, 81720108031]
- CAS Strategic Priority Research Programs [XDB37030100, XDB37040102]
- Agence Nationale de la Recherche [ANR 18-CE11-0004-01]
- Fondation Recherche Medicale [DEQ20170336747, ANR-15-CE18-0020-01]
- CNRS PRC [1403]
- Inserm IRP BrainSignal
- Agence Nationale de la Recherche (ANR) [ANR-15-CE18-0020, ANR-18-CE11-0004] Funding Source: Agence Nationale de la Recherche (ANR)
Metabotropic glutamate receptors play a key role in modulating synaptic transmission and neuronal excitability in the central nervous system. The study reveals distinct structural and functional features of mGlu2 and mGlu7 subtypes, highlighting the importance of receptor activation and signaling. Furthermore, the dominant role of mGlu7 in controlling dimeric association and G-protein activation in the heterodimer indicates a complex landscape of mGlu dimerization and activation.
The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system1. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties(2-4). Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.
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