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

doi:10.1038/s41586-020-2019-0

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2019-0
	Structural basis of ligand recognition and self-activation of orphan GPR52
	Liu, Guoxia 1; Papa, Arianne 2; Katchman, Alexander N.1; Zakharov, Sergey I.1; Roybal, Daniel 3; Hennessey, Jessica A.1; Kushner, Jared 1; Yang, Lin 1; Chen, Bi-Xing 1; Kushnir, Alexander 1; Dangas, Katerina 1; Gygi, Steven P.4; Pitt, Geoffrey S.5; Colecraft, Henry M.2,3; Ben-Johny, Manu 2; Kalocsay, Marian 6; Marx, Steven O.1,3
	2020-01-22
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	Peoples R China; USA
英文关键词	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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000517050000006
WOS关键词	CRYO-EM STRUCTURE ; PROTEIN-COUPLED RECEPTORS ; BETA(2)-ADRENERGIC RECEPTOR ; CRYSTAL-STRUCTURE ; IONIC LOCK ; AGONIST ; DISCOVERY ; CRYSTALLIZATION ; STABILIZATION ; MUTAGENESIS
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281501
专题	地球科学资源环境科学气候变化
作者单位	1.Columbia Univ, Dept Med, Vagelos Coll Phys & Surg, Div Cardiol, New York, NY 10032 USA; 2.Columbia Univ, Dept Physiol & Cellular Biophys, Vagelos Coll Phys & Surg, New York, NY USA; 3.Columbia Univ, Dept Pharmacol, Vagelos Coll Phys & Surg, New York, NY 10032 USA; 4.Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA; 5.Weill Cornell Med Coll, Cardiovasc Res Inst, New York, NY USA; 6.Harvard Med Sch, Lab Syst Pharmacol, Dept Syst Biol, Boston, MA 02115 USA
推荐引用方式 GB/T 7714	Liu, Guoxia,Papa, Arianne,Katchman, Alexander N.,et al. Structural basis of ligand recognition and self-activation of orphan GPR52[J]. NATURE,2020.
APA	Liu, Guoxia.,Papa, Arianne.,Katchman, Alexander N..,Zakharov, Sergey I..,Roybal, Daniel.,...&Marx, Steven O..(2020).Structural basis of ligand recognition and self-activation of orphan GPR52.NATURE.
MLA	Liu, Guoxia,et al."Structural basis of ligand recognition and self-activation of orphan GPR52".NATURE (2020).