Two disparate ligand-binding sites in the human P2Y(1) receptor
文献类型：期刊论文
| 作者 | Zhang, Dandan2; Gao, Zhan-Guo3; Zhang, Kaihua2; Kiselev, Evgeny3; Crane, Steven3; Wang, Jiang2 ; Paoletta, Silvia3; Yi, Cuiying2; Ma, Limin2; Zhang, Wenru2
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| 刊名 | NATURE
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| 出版日期 | 2015-04-16 |
| 卷号 | 520期号:7547页码:317-+ |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/nature14287 |
| 文献子类 | Article |
| 英文摘要 | In response to adenosine 59-diphosphate, the P2Y(1) receptor (P2Y(1)R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y(1)R in complex with a nucleotide antagonist MRS2500 at 2.7 angstrom resolution, and with a non-nucleotide antagonist BPTU at 2.2 angstrom resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y(1)R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y(1)R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y(12)R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolutioninsights into P2Y(1)R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; CRYSTAL-STRUCTURE ; NUCLEOTIDE RECEPTORS ; PURINERGIC RECEPTORS ; SMALL-MOLECULE ; ANTAGONISTS ; AGONIST ; DISCOVERY ; COMPLEX ; RECOGNITION |
| 资助项目 | National Basic Research Program of China[2012CB518000] ; National Basic Research Program of China[2014CB910400] ; National Basic Research Program of China[2012CB910400] ; CAS Strategic Priority Research Program[XDB08020300] ; National Science Foundation of China[31422017] ; National Science Foundation of China[31370729] ; National Science Foundation of China[91313000] ; National Science and Technology Major Project[2013ZX09507001] ; NIDDK[00000000] ; NIH Intramural Research Program[Z01 DK031116-26] ; National Institutes of Health[U54 GM094618] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000352974200031 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276571]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Wu, Beili |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA; 4.Univ So Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA; 5.Univ So Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA; 6.ShanghaiTech Univ, iHuman Inst, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Dandan,Gao, Zhan-Guo,Zhang, Kaihua,et al. Two disparate ligand-binding sites in the human P2Y(1) receptor[J]. NATURE,2015,520(7547):317-+. |
| APA | Zhang, Dandan.,Gao, Zhan-Guo.,Zhang, Kaihua.,Kiselev, Evgeny.,Crane, Steven.,...&Wu, Beili.(2015).Two disparate ligand-binding sites in the human P2Y(1) receptor.NATURE,520(7547),317-+. |
| MLA | Zhang, Dandan,et al."Two disparate ligand-binding sites in the human P2Y(1) receptor".NATURE 520.7547(2015):317-+. |
入库方式： OAI收割
来源：上海药物研究所
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