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Agonist-bound structure of the human P2Y_(12) receptor

机译：人类P2Y_（12）受体的激动剂结合结构

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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, 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 A resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 A 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), 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 in the δ-group of dass A G-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.
机译：P2Y_（12）受体（P2Y_（12）R）是在人类中表达的P2YR家族的八个成员之一，是抑制血小板聚集的最主要的临床药物靶标之一。尽管对P2Y_（12）R的诱变和建模研究提供了对配体结合的有用见解，但在分子水平上对P2Y_（12）R的激动剂和拮抗剂的识别和功能仍然知之甚少。在这里，我们报道了在2.5 A分辨率下与完整的激动剂2-甲硫基腺苷-5'-二磷酸酯（2MeSADP，内源性激动剂ADP的紧密类似物）复合的人P2Y_（12）R的结构，以及相应的ATP衍生物2-甲硫基腺苷5'-三磷酸酯（2MeSATP），分辨率为3.1 A.这些结构以及与拮抗剂乙基6-（4-（（（苄基磺酰基）氨基甲酰基）哌啶-1-基）-5-氰基-2-甲基烟酸酯（AZD1283）的P2Y_（12）R的结构揭示了惊人的构象变化在细胞外区域中的核苷酸和非核苷酸配体复合物之间存在一个差异。对这些变化的进一步分析提供了对das A G蛋白偶联受体（GPCR）δ组中独特配体结合态势的了解。激动剂和非核苷酸拮抗剂在P2Y_（12）R中采用不同的方向，只有部分重叠的结合口袋。激动剂结合的P2Y_（12）R结构回答了围绕P2Y_（12）R激动剂识别的长期存在的问题，并揭示了与尚未报道参与激动剂结合的几个残基的相互作用。就我们所知，第一个例子是GPCR，其中激动剂进入结合口袋需要在高度延展性的细胞外区域进行大规模重排，因此结构和对接研究将提供对GRP的药理学和作用机制的宝贵见解。 P2Y_（12）R以及可能与其他紧密相关的P2YR的激动剂和不同类型的拮抗剂。

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  • 来源
    《Nature》 |2014年第7498期|119-122|共4页
  • 作者

    Jin Zhang; Kaihua Zhang; Zhan-Guo Gao; Silvia Paoletta; Dandan Zhang; Gye Won Han; Tingting Li; Limin Ma; Wenru Zhang; Christa E. Mueller; Huaiyu Yang; Hualiang Jiang; Vadim Cherezov; Vsevolod Katritch; Kenneth A. Jacobson; Raymond C. Stevens; Beili Wu; Qiang Zhao;

  • 作者单位

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    PharmaCenter Bonn, University of Bonn, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany;

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA;

    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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