. 2021 Jun;594(7864):583-588.

doi: 10.1038/s41586-021-03495-2. Epub 2021 Jun 16.

Structures of G_i-bound metabotropic glutamate receptors mGlu2 and mGlu4

Shuling Lin^#^{1

2}, Shuo Han^#³, Xiaoqing Cai^#^{1

4}, Qiuxiang Tan¹, Kexiu Zhou^{1

2

5}, Dejian Wang^{2

3}, Xinwei Wang^{1

2}, Juan Du⁶, Cuiying Yi³, Xiaojing Chu¹, Antao Dai^{1

4}, Yan Zhou^{1

4}, Yan Chen⁷, 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

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. mwwang@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, China. mwwang@simm.ac.cn.
¹² The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
¹³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. mwwang@simm.ac.cn.
¹⁴ School of Pharmacy, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁵ School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁶ University of Chinese Academy of Sciences, Beijing, China. zhaoq@simm.ac.cn.
¹⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoq@simm.ac.cn.
¹⁸ Zhongshan Branch, Institute of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China. zhaoq@simm.ac.cn.
¹⁹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
²⁰ University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
²¹ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.
²² School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. beiliwu@simm.ac.cn.

^# Contributed equally.

PMID: 34135510
DOI: 10.1038/s41586-021-03495-2

Structures of G_i-bound metabotropic glutamate receptors mGlu2 and mGlu4

Shuling Lin et al. Nature. 2021 Jun.

. 2021 Jun;594(7864):583-588.

doi: 10.1038/s41586-021-03495-2. Epub 2021 Jun 16.

Authors

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. mwwang@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, China. mwwang@simm.ac.cn.
¹² The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
¹³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. mwwang@simm.ac.cn.
¹⁴ School of Pharmacy, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁵ School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁶ University of Chinese Academy of Sciences, Beijing, China. zhaoq@simm.ac.cn.
¹⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoq@simm.ac.cn.
¹⁸ Zhongshan Branch, Institute of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China. zhaoq@simm.ac.cn.
¹⁹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
²⁰ University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
²¹ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.
²² School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. beiliwu@simm.ac.cn.

^# 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 G_i 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-G_i 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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Cyro-EM structure of human mGlus: leading therapeutic potential to neurological diseases.
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Structures of G_i-bound metabotropic glutamate receptors mGlu2 and mGlu4

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Structures of G_i-bound metabotropic glutamate receptors mGlu2 and mGlu4

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