Structure of the human P2Y12 receptor in complex with an antithrombotic drug.
Structure of the human P2Y12 receptor in complex with an antithrombotic drug.
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人 P2Y(12) 受体与抗血栓药物复合物的结构
作者：
P2 Y受体（P2 YRs）是嘌呤能G蛋白偶联受体（GPCRs）的一个家族，由细胞外核苷酸激活。在人类中总共有八种不同功能的P2 YR，其被细分为P2 Y1样受体和P2 Y12样受体。它们的配体通常是带电荷的分子，在体内的生物利用度和稳定性相对较低，这限制了我们对该受体家族的了解。P2 Y12 R调节血小板活化和血栓形成，几种靶向P2 Y12 R的抗血栓形成药物-包括代谢和共价结合的前药氯吡格雷（Plastine）和普拉格雷（Effient），以及直接作用于受体的核苷类似物替格瑞洛（Brilinta）-已被批准用于预防中风和心肌梗死。然而，这些药物的局限性（例如，氯吡格雷作用的半衰期很长和替格瑞洛的特征性不良反应特征）表明，开发新一代P2 Y12 R抑制剂的医学需求尚未得到满足。在这里，我们报告了2.6 nm分辨率的晶体结构的人P2 Y12 R与非核苷酸可逆拮抗剂，AZD 1283的复合物。该结构揭示了螺旋V的独特的直链构象，这将P2 Y12 R与所有其他已知的A类GPCR结构分开。结合AZD 1283后，未观察到螺旋III和细胞外环2之间的GPCR中高度保守的二硫桥，并且似乎是动态的。沿着AZD 1283结合位点的细节，细胞外界面的分析揭示了相邻的配体结合区域，并表明两个口袋可能是二核苷酸结合所必需的。该结构为开发改进的P2 Y12 R配体和变构调节剂作为候选药物提供了重要的见解。
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 receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our under-standing of this receptor family. P2Y12R regulates platelet activation and thrombus formation, 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) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. 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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