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Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

文献类型：期刊论文

作者Lin, Shuling1,2; Han, Shuo3; Cai, Xiaoqing1,4; Tan, Qiuxiang1; Zhou, Kexiu1,2,5; Wang, Dejian2,3; Wang, Xinwei1,2; Du, Juan6; Yi, Cuiying3; Chu, Xiaojing1
刊名NATURE
出版日期2021-06-16
页码23
ISSN号0028-0836
DOI10.1038/s41586-021-03495-2
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Zhao, Qiang(zhaoq@simm.ac.cn) ; Wu, Beili(beiliwu@simm.ac.cn)
英文摘要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 activation(2). 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.
WOS关键词LIGAND-INDUCED REARRANGEMENT ; 3RD INTRACELLULAR LOOPS ; PHARMACOLOGICAL CHARACTERIZATION ; ALLOSTERIC MODULATOR ; HEPTAHELICAL DOMAIN ; POTENT ; IDENTIFICATION ; ACTIVATION ; BINDING ; COOPERATIVITY
资助项目National Science Foundation of China[31825010] ; National Science Foundation of China[81872915] ; National Science Foundation of China[82073904] ; National Science Foundation of China[81773792] ; National Science Foundation of China[81973373] ; National Key R&D Program of China[2018YFA0507000] ; CAS Strategic Priority Research Program[XDB37030100] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000662148600004
出版者NATURE RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/297099]  
专题新药研究国家重点实验室
通讯作者Wang, Ming-Wei; Zhao, Qiang; Wu, Beili
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
7.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
8.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Int Res Ctr Sensory Biol & Technol MOST, Key Lab Mol Biophys MOE, Wuhan, Peoples R China
9.Guangzhou Regenerat Med & Hlth Guangdong Lab, Bioland Lab, Guangzhou, Peoples R China
10.Fudan Univ, Sch Basic Med Sci, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Lin, Shuling,Han, Shuo,Cai, Xiaoqing,et al. Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4[J]. NATURE,2021:23.
APA Lin, Shuling.,Han, Shuo.,Cai, Xiaoqing.,Tan, Qiuxiang.,Zhou, Kexiu.,...&Wu, Beili.(2021).Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4.NATURE,23.
MLA Lin, Shuling,et al."Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4".NATURE (2021):23.

入库方式： OAI收割

来源：上海药物研究所

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