Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

Shuling Lin, Shuo Han, Xiaoqing Cai, Qiuxiang Tan, Kexiu Zhou, Dejian Wang, Xinwei Wang, Juan Du, Cuiying Yi, Xiaojing Chu, Antao Dai, Yan Zhou, Yan Chen, Yu Zhou, Hong Liu, Jianfeng Liu, Dehua Yang, Ming-Wei Wang (), Qiang Zhao () and Beili Wu ()
Additional contact information
Shuling Lin: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Shuo Han: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaoqing Cai: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qiuxiang Tan: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Kexiu Zhou: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Dejian Wang: University of Chinese Academy of Sciences
Xinwei Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Juan Du: University of Chinese Academy of Sciences
Cuiying Yi: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaojing Chu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Antao Dai: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yan Zhou: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yan Chen: Fudan University
Yu Zhou: University of Chinese Academy of Sciences
Hong Liu: University of Chinese Academy of Sciences
Jianfeng Liu: Huazhong University of Science and Technology
Dehua Yang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ming-Wei Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qiang Zhao: University of Chinese Academy of Sciences
Beili Wu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature, 2021, vol. 594, issue 7864, 583-588

Abstract: Abstract The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system)1. It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation2. However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric Gi protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu–Gi structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs.

Date: 2021
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DOI: 10.1038/s41586-021-03495-2

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