Two disparate ligand-binding sites in the human P2Y(1) receptor

doi:10.1038/nature14287

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

	Two disparate ligand-binding sites in the human P2Y(1) receptor
	Zhang, Dandan 1; Gao, Zhan-Guo 2; Zhang, Kaihua 1; Kiselev, Evgeny 2; Crane, Steven 2; Wang, Jiang 1; Paoletta, Silvia 2; Yi, Cuiying 1; Ma, Limin 1; Zhang, Wenru 1; Han, Gye Won 3; Liu, Hong 1; Cherezov, Vadim 3; Katritch, Vsevolod 4; Jiang, Hualiang 5; Stevens, Raymond C.3,6 ; Jacobson, Kenneth A.2; Zhao, Qiang 1; Wu, Beili1
	2015-04-16
发表期刊	NATURE
ISSN	0028-0836
卷号	520 期号:7547 页码:317-+
发表状态	已发表
DOI	10.1038/nature14287
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.
收录类别	SCI
语种	英语
资助项目	National Institutes of Health[U54 GM094618]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000352974200031
出版者	NATURE PUBLISHING GROUP
WOS关键词	PROTEIN-COUPLED RECEPTORS ; CRYSTAL-STRUCTURE ; NUCLEOTIDE RECEPTORS ; PURINERGIC RECEPTORS ; SMALL-MOLECULE ; ANTAGONISTS ; AGONIST ; DISCOVERY ; COMPLEX ; RECOGNITION
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/2224
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.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA 3.Univ So Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA 4.Univ So Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA 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, 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-+.