Agonist-bound structure of the human P2Y12 receptor.
Agonist-bound structure of the human P2Y12 receptor.
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人 P2Y(12) 受体激动剂结合结构
DOI：
10.1038/nature13288
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发表时间：
2014-05-01
期刊：
影响因子：
64.8
通讯作者：
Zhao, Qiang
中科院分区：
文献类型：
--
作者：
Zhang, Jin;Zhang, Kaihua;Gao, Zhan-Guo;Paoletta, Silvia;Zhang, Dandan;Han, Gye Won;Li, Tingting;Ma, Limin;Zhang, Wenru;Mueller, Christa E.;Yang, Huaiyu;Jiang, Hualiang;Cherezov, Vadim;Katritch, Vsevolod;Jacobson, Kenneth A.;Stevens, Raymond C.;Wu, Beili;Zhao, Qiang
P2 Y12受体（P2 Y12 R）是人类表达的P2 YR家族的八个成员之一，已被鉴定为抑制血小板聚集的最突出的临床药物靶标之一。因此，广泛的诱变和建模研究的P2 Y12 R已经揭示了激动剂/拮抗剂结合的许多方面。然而，激动剂和拮抗剂的识别和功能在P2 Y12 R的细节仍然知之甚少，在分子水平上。在这里，我们报告了人P2 Y12 R与完全激动剂2-甲硫基-腺苷-5 ′-二磷酸（2 MeSADP，内源性激动剂ADP的类似物）复合物的结构（2.5 μ m分辨率），以及相应的ATP衍生物2-甲硫基-腺苷-5 ′-三磷酸（2 MeSATP）（3.1 μ m分辨率）。这些结构的分析，连同P2 Y12 R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（AZD 1283），揭示了细胞外区域中核苷酸和非核苷酸配体复合物之间的显著构象变化，提供了对A类G蛋白偶联受体（GPCR）的δ-组中不同配体结合景观的第一次洞察。激动剂和非核苷酸拮抗剂在P2 Y12 R中采用不同的取向，只有部分重叠的结合口袋。激动剂结合的P2 Y12 R结构回答了围绕P2 Y12 R-激动剂识别的长期存在的模糊性，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。作为GPCR的第一个例子，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中进行大规模重排，因此结构研究将为P2 Y12 R和潜在的其他密切相关的P2 YR的激动剂和不同类别的拮抗剂的药理学和作用机制提供宝贵的见解。
The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, has been identified as one of the most prominent clinical drug targets for inhibition of platelet aggregation. Consequently, extensive mutagenesis and modeling studies of the P2Y12R have revealed many aspects of agonist/antagonist binding. However, the details of 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 a 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. Analysis of these structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283), reveals dramatic conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions, providing the first insight into a different 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 ambiguities 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 of a GPCR where agonist access to the binding pocket requires large scale rearrangements in the highly malleable extracellular region, the structural studies therefore will 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.
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