Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6

Determination of the crystal structure of the zebrafish LPA6 receptor shows that the lipid ligand binds to an unusual ligand-binding pocket in the receptor that is laterally accessible through the membrane. The lysophosphatidic acid (LPA) receptors are a group of G-protein-coupled receptors (GPCRs) implicated in the development of cancer and fibrosis. The six LPA receptors consist of LPA1–LPA3 and the recently discovered LPA4–LPA6. LPA4–LPA6 are interesting potential therapeutic targets—the LPA6 gene deletion, for example, results in congenital hair loss—but lack of structural data has hampered research efforts in this area. Here, Osamu Nureki and colleagues report the crystal structure of the zebrafish LPA6 receptor, which contains an unusual ligand binding pocket that is open to the cell membrane. The authors propose that the lipid ligand binds to this lateral pocket. This work provides information on ligand recognition and could inform potential drug discovery efforts. 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-protein-coupled receptors to provoke various cellular reactions1. Because LPA signalling has been implicated in cancer2 and fibrosis3, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1–LPA3)1 and the phylogenetically distant non-EDG family (LPA4–LPA6)4. The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors5. 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 receptors4, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures6,7,8 because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 A crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss9,10, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 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.