Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
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DOI：
10.1038/nature23448
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发表时间：
2017-08-17
期刊：
影响因子：
64.8
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
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作者：
Taniguchi, Reiya;Inoue, Asuka;Nureki, Osamu
溶血磷脂酸（LPA）是一种生物活性脂质，由磷酸基团、甘油骨架和长度和饱和度不同的单个酰基链组成。LPA激活六种A类G蛋白偶联受体，引发各种细胞反应（1）。由于LPA信号传导与癌症（2）和纤维化（3）有关，因此LPA受体被认为是有前途的药物靶点。六种LPA受体被细分为内皮分化基因（EDG）家族（LPA（1）-LPA（3））（1）和遗传学上远缘的非EDG家族（LPA（4）-LPA（6））（4）。LPA的结构（1）增强了我们对LPA受体EDG家族的理解（5）。相比之下，由于缺乏结构信息，LPA受体的非EDG家族的功能和药理学特征仍然未知。尽管非EDG LPA受体与P2 Y家族的核苷酸受体具有序列相似性（4），但由于其配体的化学结构存在很大差异，因此不能从P2 Y（1）和P2 Y（12）结构推断出LPA识别机制（6-8）。在这里，我们确定了LPA的3.2埃晶体结构（6），其基因缺失导致先天性脱发（9，10），以阐明LPA受体的非EDG家族的配体识别机制。值得注意的是，LPA（6）的配体结合口袋朝向膜横向开放，并且用于结晶的脂质的酰基链结合在该口袋内，表明LPA酰基链的结合模式。对接和诱变分析也表明，中央空腔内的保守的带正电荷的残基识别磷酸头基的LPA通过诱导跨膜螺旋6和7的向内移动，这表明受体的激活是由这种构象重排触发。
Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-proteincoupled receptors to provoke various cellular reactions(1). Because LPA signalling has been implicated in cancer(2) and fibrosis(3), the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA(1)-LPA(3))(1) and the phylogenetically distant nonEDG family (LPA(4)-LPA(6))(4). The structure of LPA(1) has enhanced our understanding of the EDG family of LPA receptors(5). By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors(4), the LPA recognition mechanism cannot be deduced from the P2Y(1) and P2Y(12) structures(6-8) because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 angstrom crystal structure of LPA(6), the gene deletion of which is responsible for congenital hair loss(9,10), to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA(6) is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.