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Publication Abstract from PubMed

Lysophosphatidic acid receptor 1 (LPA(1)) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA(1) is a drug target for various diseases, including cancer, inflammation, and neuropathic pain. Notably, LPA(1) agonists have potential therapeutic value for obesity and urinary incontinence. Here, we report a cryo-electron microscopy structure of the active human LPA(1)-G(i) complex bound to ONO-0740556, an LPA analog with more potent activity against LPA(1). Our structure elucidated the details of the agonist binding mode and receptor activation mechanism mediated by rearrangements of transmembrane segment 7 and the central hydrophobic core. A structural comparison of LPA(1) and other phylogenetically-related lipid-sensing GPCRs identified the structural determinants for lipid preference of LPA(1). Moreover, we characterized the structural polymorphisms at the receptor-G-protein interface, which potentially reflect the G-protein dissociation process. Our study provides insights into the detailed mechanism of LPA(1) binding to agonists and paves the way toward the design of drug-like agonists targeting LPA(1).

Structure of the active G(i)-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist.,Akasaka H, Tanaka T, Sano FK, Matsuzaki Y, Shihoya W, Nureki O Nat Commun. 2022 Sep 15;13(1):5417. doi: 10.1038/s41467-022-33121-2. PMID:36109516^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.