Two disparate ligand-binding sites in the human P2Y(1) receptor
Zhang, Dandan1; Gao, Zhan-Guo2; Zhang, Kaihua1; Kiselev, Evgeny2; Crane, Steven2; Wang, Jiang1; Paoletta, Silvia2; Yi, Cuiying1; Ma, Limin1; Zhang, Wenru1; Han, Gye Won3; Liu, Hong1; Cherezov, Vadim3; Katritch, Vsevolod4; Jiang, Hualiang5; Stevens, Raymond C.3,6; Jacobson, Kenneth A.2; Zhao, Qiang1; Wu, Beili1
2015-04-16
Source PublicationNATURE
ISSN0028-0836
Volume520Issue:7547Pages:317-+
Status已发表
DOI10.1038/nature14287
AbstractIn 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.
Indexed BySCI
Language英语
Funding ProjectNational Institutes of Health[U54 GM094618]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000352974200031
PublisherNATURE PUBLISHING GROUP
WOS KeywordPROTEIN-COUPLED RECEPTORS ; CRYSTAL-STRUCTURE ; NUCLEOTIDE RECEPTORS ; PURINERGIC RECEPTORS ; SMALL-MOLECULE ; ANTAGONISTS ; AGONIST ; DISCOVERY ; COMPLEX ; RECOGNITION
Original Document TypeArticle
Citation statistics
Cited Times:217[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2224
CollectioniHuman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
Corresponding AuthorWu, Beili
Affiliation1.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
Recommended Citation
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-+.
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