Structural highlights
Function
GNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
- ↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
- ↑ Akasaka H, Tanaka T, Sano FK, Matsuzaki Y, Shihoya W, Nureki O. Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist. Nat Commun. 2022 Sep 15;13(1):5417. doi: 10.1038/s41467-022-33121-2. PMID:36109516 doi:http://dx.doi.org/10.1038/s41467-022-33121-2
