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Structural basis of ligand recognition and self-activation of orphan GPR52

文献类型：期刊论文

作者Lin, Xi1,2,3,4; Li, Mingyue2,3,4; Wang, Niandong1,2,3,4; Wu, Yiran1; Luo, Zhipu5; Guo, Shimeng6; Han, Gye-Won7; Li, Shaobai8,9; Yue, Yang1; Wei, Xiaohu2,3,4
刊名NATURE
出版日期2020-02-19
页码21
ISSN号0028-0836
DOI10.1038/s41586-020-2019-0
通讯作者Wu, Jian(wujian@shsmu.edu.cn) ; Lei, Ming(leim@shsmu.edu.cn) ; Xu, Fei(xufei@shanghaitech.edu.cn)
英文摘要Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor. GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders(1,2). Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G(s) protein(2), but it is unclear how GPR52 and G(s) couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G(s)-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52(3). A fully active state is achieved when G(s) is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.
WOS关键词CRYO-EM STRUCTURE ; PROTEIN-COUPLED RECEPTORS ; BETA(2)-ADRENERGIC RECEPTOR ; CRYSTAL-STRUCTURE ; IONIC LOCK ; AGONIST ; DISCOVERY ; CRYSTALLIZATION ; STABILIZATION ; MUTAGENESIS
资助项目National Key Research and Development Program of China[2018YFA0507000] ; National Natural Science Foundation of China[31525007] ; National Natural Science Foundation of China[81861128023] ; National Natural Science Foundation of China[31971178] ; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support[20181711] ; Shanghai Outstanding Academic Leader funding[19XD1422800]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000517050000006
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/281300]  
专题中国科学院上海药物研究所
通讯作者Wu, Jian; Lei, Ming; Xu, Fei
作者单位1.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Soochow Univ, Sch Biol & Basic Med Sci, Inst Mol Enzymol, Suzhou, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai, Peoples R China
7.Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA USA
8.Shanghai Jiao Tong Univ, Peoples Hosp 9, Sch Med, Shanghai, Peoples R China
9.Shanghai Inst Precis Med, Shanghai, Peoples R China
10.Shanghai Key Lab Translat Med Ear & Nose Dis, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Lin, Xi,Li, Mingyue,Wang, Niandong,et al. Structural basis of ligand recognition and self-activation of orphan GPR52[J]. NATURE,2020:21.
APA Lin, Xi.,Li, Mingyue.,Wang, Niandong.,Wu, Yiran.,Luo, Zhipu.,...&Xu, Fei.(2020).Structural basis of ligand recognition and self-activation of orphan GPR52.NATURE,21.
MLA Lin, Xi,et al."Structural basis of ligand recognition and self-activation of orphan GPR52".NATURE (2020):21.

入库方式： OAI收割

来源：上海药物研究所

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