2. Academic Validation
  3. Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

  • Nature. 2021 Jun;594(7864):583-588. doi: 10.1038/s41586-021-03495-2.
Shuling Lin # 1 2,  Shuo Han # 3,  Xiaoqing Cai # 1 4,  Qiuxiang Tan 1,  Kexiu Zhou 1 2 5,  Dejian Wang 2 3,  Xinwei Wang 1 2,  Juan Du 6,  Cuiying Yi 3,  Xiaojing Chu 1,  Antao Dai 1 4,  Yan Zhou 1 4,  Yan Chen 7,  Yu Zhou 2 3,  Hong Liu 2 3 5,  Jianfeng Liu 8 9,  Dehua Yang 1 2 4,  Ming-Wei Wang 10 11 12 13 14 15,  Qiang Zhao 16 17 18,  Beili Wu 19 20 21 22
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 7 School of Pharmacy, Fudan University, Shanghai, China.
  • 8 Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
  • 10 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 12 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 13 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 14 School of Pharmacy, Fudan University, Shanghai, China. [email protected].
  • 15 School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • 16 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 17 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 18 Zhongshan Branch, Institute of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China. [email protected].
  • 19 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 20 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 21 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 22 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 34135510 DOI: 10.1038/s41586-021-03495-2
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.

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