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

doi:10.1038/s41586-020-2019-0

	Structural basis of ligand recognition and self-activation of orphan GPR52
	Lin, Xi 1,2,3,4; Li, Mingyue 1,3,4; Wang, Niandong 1,2,3,4; Wu, Yiran 2; Luo, Zhipu 5; Guo, Shimeng 6; Han, Gye-Won 7; Li, Shaobai 8,9; Yue, Yang 2; Wei, Xiaohu 1,3,4
刊名	NATURE
	2020-02-19
页码	21
ISSN号	0028-0836
DOI	10.1038/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.
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关键词	CRYO-EM STRUCTURE ; PROTEIN-COUPLED RECEPTORS ; BETA(2)-ADRENERGIC RECEPTOR ; CRYSTAL-STRUCTURE ; IONIC LOCK ; AGONIST ; DISCOVERY ; CRYSTALLIZATION ; STABILIZATION ; MUTAGENESIS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000517050000006
内容类型	期刊论文
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, Sch Life Sci & Technol, Shanghai, Peoples R China 2.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, 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.