Agonist-bound structure of the human P2Y(12) receptor

doi:10.1038/nature13288

KMS > iHuman研究所 > 特聘教授组 > Raymond Stevens组

	Agonist-bound structure of the human P2Y(12) receptor
	Zhang, Jin 1; Zhang, Kaihua 1; Gao, Zhan-Guo 2; Paoletta, Silvia 2; Zhang, Dandan 1; Han, Gye Won 3; Li, Tingting 1; Ma, Limin 1; Zhang, Wenru 1; Mueller, Christa E.4; Yang, Huaiyu 5; Jiang, Hualiang 5; Cherezov, Vadim 3; Katritch, Vsevolod 3; Jacobson, Kenneth A.2; Stevens, Raymond C.3,6 ; Wu, Beili1 ; Zhao, Qiang 1
	2014-05
发表期刊	NATURE
ISSN	0028-0836
卷号	509 期号:7498 页码:119-122
发表状态	已发表
DOI	10.1038/nature13288
摘要	The P2Y(12) receptor (P2Y(12)R), one of eight members of the P2YR family expressed in humans, is one of the most prominent clinical drug targets for inhibition of platelet aggregation. Although mutagenesis and modelling studies of the P2Y(12)R provided useful insights into ligand binding(1-4), the agonist and antagonist recognition and function at the P2Y(12)R remain poorly understood at the molecular level. Here we report the structures of the human P2Y(12)R in complex with the full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 angstrom resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 angstrom resolution. These structures, together with the structure of the P2Y(12)R with antagonist ethyl 6-(4-((benzylsulfonyl) carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283)(5), reveal striking conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions. Further analysis of these changes provides insight into a distinct ligand binding landscape inthed-group of class AG-protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y(12)R, with only partially overlapped binding pockets. The agonist-bound P2Y(12)R structure answers long-standing questions surrounding P2Y(12)R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example, to our knowledge, of a GPCR in which agonist access to the binding pocket requires large-scale rearrangements in the highly malleable extracellular region, the structural and docking studies will therefore provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y(12)R and potentially for other closely related P2YRs.
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[91313000]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000335199100051
出版者	NATURE PUBLISHING GROUP
WOS关键词	PROTEIN-COUPLED RECEPTOR ; MUSCARINIC ACETYLCHOLINE-RECEPTOR ; RESOLUTION CRYSTAL-STRUCTURE ; A(2A) ADENOSINE RECEPTOR ; MEMBRANE-PROTEINS ; IDENTIFICATION ; ANTAGONISTS ; ACTIVATION ; RHODOPSIN ; COMPLEX
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2406
专题	iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所生命科学与技术学院_特聘教授组_吴蓓丽组
通讯作者	Wu, Beili
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA 3.Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA 4.Univ Bonn, PharmaCtr Bonn, D-53121 Bonn, Germany 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 6.ShanghaiTech Univ, IHuman Inst, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Jin,Zhang, Kaihua,Gao, Zhan-Guo,et al. Agonist-bound structure of the human P2Y(12) receptor[J]. NATURE,2014,509(7498):119-122.
APA	Zhang, Jin.,Zhang, Kaihua.,Gao, Zhan-Guo.,Paoletta, Silvia.,Zhang, Dandan.,...&Zhao, Qiang.(2014).Agonist-bound structure of the human P2Y(12) receptor.NATURE,509(7498),119-122.
MLA	Zhang, Jin,et al."Agonist-bound structure of the human P2Y(12) receptor".NATURE 509.7498(2014):119-122.