Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers

doi:10.1038/s41422-023-00830-2

	Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers
	Wang, Xinwei 1,2; Wang, Mu1,3 ; Xu, Tuo 1,2; Feng, Ye1,3 ; Shao, Qiang 1,2; Han, Shuo 1,2,4; Chu, Xiaojing 1; Xu, Yechun 1,2,4; Lin, Shuling 1; Zhao, Qiang 1,2,5; Wu, Beili1,2,3,4
	2023-06-01
发表期刊	CELL RESEARCH
ISSN	1001-0602
EISSN	1748-7838
发表状态	已发表
DOI	10.1038/s41422-023-00830-2
摘要	Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.
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收录类别	SCI
语种	英语
资助项目	National Key R&D Program of China[2022YFA1302900] ; National Natural~Science Foundation of China["31825010","82121005"] ; CAS Strategic Priority Research Program[XDB37030100] ; Shanghai Science and Technology Committee grant[JCYJ-SHFY-2021008] ; null[23YF1456600]
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:001002888800001
出版者	SPRINGERNATURE
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/312313
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_吴蓓丽组生命科学与技术学院_博士生
通讯作者	Lin, Shuling; Zhao, Qiang; Wu, Beili
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Zhejiang, Peoples R China 5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Guangdong, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Wang, Xinwei,Wang, Mu,Xu, Tuo,et al. Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers[J]. CELL RESEARCH,2023.
APA	Wang, Xinwei.,Wang, Mu.,Xu, Tuo.,Feng, Ye.,Shao, Qiang.,...&Wu, Beili.(2023).Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.CELL RESEARCH.
MLA	Wang, Xinwei,et al."Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers".CELL RESEARCH (2023).