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

文献类型：期刊论文

作者Zhang, Jin6; Zhang, Kaihua6; Gao, Zhan-Guo1; Paoletta, Silvia1; Zhang, Dandan6; Han, Gye Won3; Li, Tingting6; Ma, Limin6; Zhang, Wenru6; Mueller, Christa E.4
刊名NATURE
出版日期2014-05-01
卷号509期号:7498页码:119-122
ISSN号0028-0836
DOI10.1038/nature13288
文献子类Article
英文摘要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.
WOS关键词PROTEIN-COUPLED RECEPTOR ; MUSCARINIC ACETYLCHOLINE-RECEPTOR ; RESOLUTION CRYSTAL-STRUCTURE ; A(2A) ADENOSINE RECEPTOR ; MEMBRANE-PROTEINS ; IDENTIFICATION ; ANTAGONISTS ; ACTIVATION ; RHODOPSIN ; COMPLEX
资助项目National Basic Research Program of China[2012CB910400] ; National Basic Research Program of China[2012CB518000] ; National Basic Research Program of China[2014CB910400] ; National Institutes of Health[R01AI100604] ; National Institutes of Health[U54 GM094618] ; National Science Foundation of China[31370729] ; National Science and Technology Major Project[2013ZX09507001] ; National Science and Technology Major Project[2012ZX09301001] ; National Institutes of Health NIDDK Intramural Research Program[00000000] ; National Natural Science Foundation of China[91313000]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000335199100051
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/277104]  
专题药物靶标结构与功能中心
通讯作者Wu, Beili
作者单位1.Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA;
2.ShanghaiTech Univ, IHuman Inst, Shanghai 201203, Peoples R China
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.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 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.

入库方式： OAI收割

来源：上海药物研究所

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