Structures of G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4

doi:10.1038/s41586-021-03495-2

	Structures of G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4
	Lin, Shuling 1,2; Han, Shuo 3; Cai, Xiaoqing 1,4; Tan, Qiuxiang 1; Zhou, Kexiu 1,2,5; Wang, Dejian 2,3; Wang, Xinwei 1,2; Du, Juan 6; Yi, Cuiying ; Chu, Xiaojing 1
刊名	NATURE
	2021-06-24
卷号	594 期号:7864 页码:583-+
ISSN号	0028-0836
DOI	10.1038/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.
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关键词	LIGAND-INDUCED REARRANGEMENT ; 3RD INTRACELLULAR LOOPS ; PHARMACOLOGICAL CHARACTERIZATION ; ALLOSTERIC MODULATOR ; HEPTAHELICAL DOMAIN ; ACTIVATION ; POTENT ; IDENTIFICATION ; BINDING ; COOPERATIVITY
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE RESEARCH
WOS记录号	WOS:000665247800023
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296799]
专题	中国科学院上海药物研究所
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, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 6.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China 7.Fudan Univ, Sch Pharm, Shanghai, Peoples R China 8.Huazhong Univ Sci & Technol, Int Res Ctr Sensory Biol & Technol MOST, Coll Life Sci & Technol, 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 G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4[J]. NATURE,2021,594(7864):583-+.
APA	Lin, Shuling.,Han, Shuo.,Cai, Xiaoqing.,Tan, Qiuxiang.,Zhou, Kexiu.,...&Wu, Beili.(2021).Structures of G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4.NATURE,594(7864),583-+.
MLA	Lin, Shuling,et al."Structures of G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4".NATURE 594.7864(2021):583-+.