Nature2014-06-18 4:24 PM

人P2Y12受体的两个晶体结构 Structure of the human P2Y12 receptor in complex with an antithrombotic drug

论文摘要 

本期Nature上的两篇论文发表了人P2Y12受体的两个晶体结构:第一个是与抗血栓药物AZD1283形成复合物状态下的结构;第二个是与一个完全激动药(内源性激动药ADP的很相近的类似物)和一个部分激动药结合在一起状态下的结构。P2Y受体是被细胞外核苷酸激活的一个家族的purinergic“G-蛋白耦合受体”(GPCRs)。P2Y12受体主要见于血小板表面上,在那里它调控血小板激活和血栓形成,同时它还是几种重要抗血栓药物的作用目标。在整个结构中,P2Y12受体被发现与其他GPCRs类似,尽管配体结合袋的性状和位置都不同寻常。对三个新确定的结构所做对比显示,激动药的结合诱导GPCR的细胞外区域发生了一个大尺度的重排。

Abstract 

P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors1. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo2, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation3, 4, and several antithrombotic drugs targeting P2Y12R—including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor—have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor)5, 6 suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors7, 8. Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.

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