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Structures of human mGlu2 and mGlu7 homo- and heterodimers

文献类型：期刊论文

作者Du, Juan1,2,3; Wang, Dejian1,4; Fan, Hongcheng4,5; Xu, Chanjuan6; Tai, Linhua4,5; Lin, Shuling2,4; Han, Shuo1; Tan, Qiuxiang2; Wang, Xinwei2,4; Xu, Tuo1,4
刊名NATURE
出版日期2021-06-24
卷号594期号:7864页码:589-+
ISSN号0028-0836
DOI10.1038/s41586-021-03641-w
通讯作者Liu, Hong(hliu@simm.ac.cn) ; Liu, Jianfeng(jfliu@mail.hust.edu.cn) ; Sun, Fei(feisun@ibp.ac.cn) ; Wu, Beili(beiliwu@simm.ac.cn) ; Zhao, Qiang(zhaoq@simm.ac.cn)
英文摘要The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system1. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties(2-4). Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.
WOS关键词METABOTROPIC GLUTAMATE RECEPTORS ; PHARMACOLOGICAL CHARACTERIZATION ; ORGANIZATION ; DISCOVERY ; POTENT
资助项目Japan Synchrotron Radiation Research Institute[2019A2543] ; Japan Synchrotron Radiation Research Institute[2019B2543] ; Japan Synchrotron Radiation Research Institute[2019A2541] ; Japan Synchrotron Radiation Research Institute[2019B2541] ; mGlu2 NAMs[NAM563] ; mGlu2 NAMs[NAM597] ; National Key R&D Program of China[2018YFA0507000] ; National Science Foundation of China[31825010] ; National Science Foundation of China[31830020] ; National Science Foundation of China[81720108031] ; CAS Strategic Priority Research Programs[XDB37030100] ; CAS Strategic Priority Research Programs[XDB37040102] ; Agence Nationale de la Recherche[ANR 18-CE11-0004-01] ; Fondation Recherche Medicale[DEQ20170336747] ; Fondation Recherche Medicale[ANR-15-CE18-0020-01] ; CNRS PRC[1403] ; Inserm IRP BrainSignal
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE RESEARCH
WOS记录号WOS:000665247800024
源URL[http://119.78.100.183/handle/2S10ELR8/296822]  
专题新药研究国家重点实验室
通讯作者Liu, Hong; Liu, Jianfeng; Sun, Fei; Wu, Beili; Zhao, Qiang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
3.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Chinese Acad Sci, Natl Lab Biomacromol, Natl Ctr Prot Sci Beijing, CAS Ctr Excellence Biomacromol,Inst Biophys, Beijing, Peoples R China
6.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Int Res Ctr Sensory Biol & Technol MOST, Key Lab Mol Biophys MOE, Wuhan, Peoples R China
7.Univ Montpellier, CNRS, INSERM, Inst Genom Fonct, Montpellier, France
8.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
9.Guangzhou Regenerat Med & Hlth Guangdong Lab, Bioland Lab, Guangzhou, Peoples R China
10.Chinese Acad Sci, Inst Biophys, Ctr Biol Imaging, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Du, Juan,Wang, Dejian,Fan, Hongcheng,et al. Structures of human mGlu2 and mGlu7 homo- and heterodimers[J]. NATURE,2021,594(7864):589-+.
APA Du, Juan.,Wang, Dejian.,Fan, Hongcheng.,Xu, Chanjuan.,Tai, Linhua.,...&Zhao, Qiang.(2021).Structures of human mGlu2 and mGlu7 homo- and heterodimers.NATURE,594(7864),589-+.
MLA Du, Juan,et al."Structures of human mGlu2 and mGlu7 homo- and heterodimers".NATURE 594.7864(2021):589-+.

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来源：上海药物研究所

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