Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist

Lysophosphatidic acid receptor 1 (LPA₁) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA₁ is a drug target for various diseases, including Cancer, inflammation, and neuropathic pain. Notably, LPA₁ agonists have potential therapeutic value for obesity and urinary incontinence. Here, we report a cryo-electron microscopy structure of the active human LPA₁-G_i complex bound to ONO-0740556, an LPA analog with more potent activity against LPA₁. 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 LPA₁ and other phylogenetically-related lipid-sensing GPCRs identified the structural determinants for lipid preference of LPA₁. 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 LPA₁ binding to agonists and paves the way toward the design of drug-like agonists targeting LPA₁.