Nature2014-06-18 4:39 PM

人P2Y12受体的两个晶体结构2 Agonist-bound structure of the human P2Y12receptor

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 

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)5, 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.

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