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

Hiroaki Akasaka, Tatsuki Tanaka, Fumiya K. Sano, Yuma Matsuzaki, Wataru Shihoya () and Osamu Nureki ()
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Hiroaki Akasaka: The University of Tokyo, Bunkyo
Tatsuki Tanaka: The University of Tokyo, Bunkyo
Fumiya K. Sano: The University of Tokyo, Bunkyo
Yuma Matsuzaki: The University of Tokyo, Bunkyo
Wataru Shihoya: The University of Tokyo, Bunkyo
Osamu Nureki: The University of Tokyo, Bunkyo

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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-Gi 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.

Date: 2022
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DOI: 10.1038/s41467-022-33121-2

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