Structures of human mGlu2 and mGlu7 homo- and heterodimers

Juan Du, Dejian Wang, Hongcheng Fan, Chanjuan Xu, Linhua Tai, Shuling Lin, Shuo Han, Qiuxiang Tan, Xinwei Wang, Tuo Xu, Hui Zhang, Xiaojing Chu, Cuiying Yi, Peng Liu, Xiaomei Wang, Yu Zhou, Jean-Philippe Pin, Philippe Rondard, Hong Liu (), Jianfeng Liu (), Fei Sun (), Beili Wu () and Qiang Zhao ()
Additional contact information
Juan Du: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Dejian Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hongcheng Fan: University of Chinese Academy of Sciences
Chanjuan Xu: Huazhong University of Science and Technology
Linhua Tai: University of Chinese Academy of Sciences
Shuling Lin: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Shuo Han: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qiuxiang Tan: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xinwei Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Tuo Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hui Zhang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaojing Chu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Cuiying Yi: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Peng Liu: Huazhong University of Science and Technology
Xiaomei Wang: Huazhong University of Science and Technology
Yu Zhou: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jean-Philippe Pin: Université de Montpellier, CNRS, INSERM
Philippe Rondard: Université de Montpellier, CNRS, INSERM
Hong Liu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jianfeng Liu: Huazhong University of Science and Technology
Fei Sun: University of Chinese Academy of Sciences
Beili Wu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qiang Zhao: Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature, 2021, vol. 594, issue 7864, 589-593

Abstract: Abstract 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 properties2–4. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03641-w

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