9ge2
From Proteopedia
Structure of GPR55 in complex with G13 and synthetic agonist ML184
Structural highlights
FunctionGNA13_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:15240885, PubMed:16705036, PubMed:16787920, PubMed:27084452). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (PubMed:12515866, PubMed:15240885). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (By similarity). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway (PubMed:16705036, PubMed:16787920, PubMed:27084452). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (PubMed:11976333).[UniProtKB:P27601][1] [2] [3] [4] [5] [6] Publication Abstract from PubMedGPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components and different lipids have been proposed as endogenous activators of GPR55, such as cannabinoids and lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy structures of the activated GPR55 in complex with heterotrimeric G(13) and two structurally diverse ligands: the putative endogenous agonist 1-palmitoyl-2-lysophosphatidylinositol (LPI) and the synthetic agonist ML184. These results reveal insights into ligand recognition at GPR55, G protein coupling and receptor activation. Notably, an orthosteric binding site opening towards the membrane is observed in both structures, enabling direct interaction of the agonists with membrane lipids. The structural observations are supported by mutagenesis and functional experiments employing G protein dissociation assays. These findings will be of importance for the structure-based development of drugs targeting GPR55. Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55.,Claff T, Ebenhoch R, Kley JT, Magarkar A, Nar H, Weichert D Nat Commun. 2025 Feb 25;16(1):1973. doi: 10.1038/s41467-025-57204-y. PMID:40000629[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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