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Structure of the human P2Y(12) receptor in complex with an antithrombotic drug
文献类型：期刊论文
| 作者 | Zhang, Kaihua6; Zhang, Jin6; Gao, Zhan-Guo5; Zhang, Dandan6; Zhu, Lan6; Han, Gye Won4; Moss, Steven M.5; Paoletta, Silvia5; Kiselev, Evgeny5; Lu, Weizhen6 |
| 刊名 | NATURE
 |
| 出版日期 | 2014-05-01 |
| 卷号 | 509期号:7498页码:115-118 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/nature13083 |
| 文献子类 | Article |
| 英文摘要 | P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y(12)-like receptors(1). Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo(2), which limits our understanding of this receptor family. P2Y(12)R regulates platelet activation and thrombus formation(3,4), and several antithrombotic drugs targeting P2Y(12)R-including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor-have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) 5,6 suggest that there is an unfulfilled medical need for developing a new generation of P2Y(12)R inhibitors(7,8). Here we report the 2.6 angstrom resolution crystal structure of human P2Y(12)R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y(12)R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y(12)R ligands and allosteric modulators as drug candidates. |
| WOS关键词 | PROTEIN-COUPLED RECEPTOR ; ACTIVE METABOLITE ; NUCLEOTIDE RECEPTORS ; CRYSTAL-STRUCTURE ; AMINO-ACIDS ; ANTAGONISTS ; IDENTIFICATION ; CLOPIDOGREL ; INHIBITION ; ACTIVATION |
| 资助项目 | National Basic Research Program of China[2012CB910400] ; National Basic Research Program of China[2012CB518000] ; National Institutes of Health (NIH)[R01 AI100604] ; National Institutes of Health (NIH)[U54 GM094618] ; National Science Foundation of China[31370729] ; National Science Foundation of China[31170683] ; National Institute of General Medical Sciences Postdoctoral Research Associate program[00000000] ; NIH National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000335199100050 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277103]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Zhao, Qiang |
| 作者单位 | 1.ShanghaiTech Univ, iHuman Inst, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.PharmaCtr Bonn, Inst Pharmaceut, D-53121 Bonn, Germany; 4.Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA; 5.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA; 6.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Kaihua,Zhang, Jin,Gao, Zhan-Guo,et al. Structure of the human P2Y(12) receptor in complex with an antithrombotic drug[J]. NATURE,2014,509(7498):115-118. |
| APA | Zhang, Kaihua.,Zhang, Jin.,Gao, Zhan-Guo.,Zhang, Dandan.,Zhu, Lan.,...&Zhao, Qiang.(2014).Structure of the human P2Y(12) receptor in complex with an antithrombotic drug.NATURE,509(7498),115-118. |
| MLA | Zhang, Kaihua,et al."Structure of the human P2Y(12) receptor in complex with an antithrombotic drug".NATURE 509.7498(2014):115-118. |
入库方式： OAI收割
来源：上海药物研究所
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