PUBLICATION
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6.
- Authors
- Taniguchi, R., Inoue, A., Sayama, M., Uwamizu, A., Yamashita, K., Hirata, K., Yoshida, M., Tanaka, Y., Kato, H.E., Nakada-Nakura, Y., Otani, Y., Nishizawa, T., Doi, T., Ohwada, T., Ishitani, R., Aoki, J., Nureki, O.
- ID
- ZDB-PUB-180123-14
- Date
- 2017
- Source
- Nature 548: 356-360 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Alopecia/congenital
- Alopecia/genetics
- Animals
- Binding Sites
- Cell Membrane/metabolism
- Crystallography, X-Ray
- HEK293 Cells
- Humans
- Ligands
- Lysophospholipids/chemistry*
- Lysophospholipids/metabolism*
- Molecular Docking Simulation
- Mutagenesis
- Phylogeny
- Protein Stability
- Protein Structure, Secondary
- Receptors, Lysophosphatidic Acid/chemistry*
- Receptors, Lysophosphatidic Acid/genetics
- Receptors, Lysophosphatidic Acid/metabolism*
- Substrate Specificity
- Zebrafish/genetics
- PubMed
- 28792932 Full text @ Nature
Citation
Taniguchi, R., Inoue, A., Sayama, M., Uwamizu, A., Yamashita, K., Hirata, K., Yoshida, M., Tanaka, Y., Kato, H.E., Nakada-Nakura, Y., Otani, Y., Nishizawa, T., Doi, T., Ohwada, T., Ishitani, R., Aoki, J., Nureki, O. (2017) Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6.. Nature. 548:356-360.
Abstract
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 reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. 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, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping