人 P2Y12 受体的激动剂结合结构,Nature

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人 P2Y12 受体的激动剂结合结构
Nature ( IF 50.5 ) Pub Date : 2014-04-30 , DOI: 10.1038/nature13288
Jin Zhang ₁ , Kaihua Zhang ₁ , Zhan-Guo Gao ₂ , Silvia Paoletta ₂ , Dandan Zhang ₃ , Gye Won Han ₄ , Tingting Li ₃ , Limin Ma ₃ , Wenru Zhang ₃ , Christa E Müller ₅ , Huaiyu Yang ₆ , Hualiang Jiang ₆ , Vadim Cherezov ₄ , Vsevolod Katritch ₄ , Kenneth A Jacobson ₂ , Raymond C Stevens ₇ , Beili Wu ₃ , Qiang Zhao ₃

Affiliation

1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China [2].
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.
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.
1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.

P2Y12 受体 (P2Y12R) 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突出的临床药物靶点之一。尽管 P2Y12R 的诱变和建模研究为配体结合提供了有用的见解，但 P2Y12R 的激动剂和拮抗剂识别和功能在分子水平上仍然知之甚少。在这里，我们报告了与全激动剂 2-甲硫基-腺苷-5'-二磷酸（2MeSADP，内源性激动剂 ADP 的紧密类似物）复合的人 P2Y12R 的结构，分辨率为 2.5 Å，以及相应的 ATP 衍生物 2-甲硫基- 5'-三磷酸腺苷 (2MeSATP)，分辨率为 3.1 Å。这些结构，连同具有拮抗剂 6-(4-((苄基磺酰基)氨基甲酰基)哌啶-1-基)-5-氰基-2-甲基烟酸乙酯 (AZD1283) 的 P2Y12R 的结构，揭示核苷酸和非核苷酸配体之间显着的构象变化胞外区域的复合物。对这些变化的进一步分析有助于深入了解 A 类 G 蛋白偶联受体 (GPCR) 的 δ 组中独特的配体结合情况。激动剂和非核苷酸拮抗剂在 P2Y12R 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 P2Y12R 结构回答了围绕 P2Y12R 激动剂识别的长期存在的问题，并揭示了与几个尚未报道参与激动剂结合的残基的相互作用。作为第一个例子，据我们所知，

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Agonist-bound structure of the human P2Y12 receptor

The P2Y12 receptor (P2Y12R), 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 P2Y12R provided useful insights into ligand binding, the agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here we report the structures of the human P2Y12R in complex with the full agonist 2-methylthio-adenosine-5′-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 Å resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5′-triphosphate (2MeSATP) at 3.1 Å resolution. These structures, together with the structure of the P2Y12R 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 class A G-protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing questions surrounding P2Y12R–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 P2Y12R and potentially for other closely related P2YRs.

更新日期：2014-04-30

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