7YU4

Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556, focused on receptor

Summary for 7YU4

• Entry DOI: 10.2210/pdb7yu4/pdb
• EMDB information: 34098
• Descriptor: Lysophosphatidic acid receptor 1, [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate (2 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43351.47

Authors

Akasaka, H.,Shihoya, W.,Nureki, O. (deposition date: 2022-08-16, release date: 2022-10-05, Last modification date: 2024-10-23)

Primary citation

Akasaka, H.,Tanaka, T.,Sano, F.K.,Matsuzaki, Y.,Shihoya, W.,Nureki, O.
Structure of the active G i -coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist.
Nat Commun, 13:5417-5417, 2022

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

PubMed: 36109516
DOI: 10.1038/s41467-022-33121-2

Experimental method

ELECTRON MICROSCOPY (3.7 Å)