9ge2

Structure of GPR55 in complex with G13 and synthetic agonist ML184

Structural highlights

9ge2 is a 5 chain structure with sequence from Aequorea victoria, Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.51Å
Ligands:	A1IKH, CLR, NAG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GNA13_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 PubMed

GPR55 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

↑ Meigs TE, Fedor-Chaiken M, Kaplan DD, Brackenbury R, Casey PJ. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002 Jul 5;277(27):24594-600. PMID:11976333 doi:10.1074/jbc.M201984200
↑ Suzuki N, Nakamura S, Mano H, Kozasa T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):733-8. PMID:12515866 doi:10.1073/pnas.0234057100
↑ Krakstad BF, Ardawatia VV, Aragay AM. A role for Galpha12/Galpha13 in p120ctn regulation. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10314-9. PMID:15240885 doi:10.1073/pnas.0401366101
↑ Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA, Casey PJ. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8173-8. PMID:16705036 doi:10.1073/pnas.0510254103
↑ Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ. A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 2006 Sep 8;281(36):26483-90. PMID:16787920 doi:10.1074/jbc.M604376200
↑ Yuan B, Cui J, Wang W, Deng K. Gα12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun. 2016 May 13;473(4):1240-1246. PMID:27084452 doi:10.1016/j.bbrc.2016.04.048
↑ Claff T, Ebenhoch R, Kley JT, Magarkar A, Nar H, Weichert D. Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55. Nat Commun. 2025 Feb 25;16(1):1973. PMID:40000629 doi:10.1038/s41467-025-57204-y

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Meigs TE, Fedor-Chaiken M, Kaplan DD, Brackenbury R, Casey PJ. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002 Jul 5;277(27):24594-600. PMID:11976333 doi:10.1074/jbc.M201984200

[2] Suzuki N, Nakamura S, Mano H, Kozasa T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):733-8. PMID:12515866 doi:10.1073/pnas.0234057100

[3] Krakstad BF, Ardawatia VV, Aragay AM. A role for Galpha12/Galpha13 in p120ctn regulation. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10314-9. PMID:15240885 doi:10.1073/pnas.0401366101

[4] Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA, Casey PJ. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8173-8. PMID:16705036 doi:10.1073/pnas.0510254103

[5] Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ. A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 2006 Sep 8;281(36):26483-90. PMID:16787920 doi:10.1074/jbc.M604376200

[6] Yuan B, Cui J, Wang W, Deng K. Gα12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun. 2016 May 13;473(4):1240-1246. PMID:27084452 doi:10.1016/j.bbrc.2016.04.048

[7] Claff T, Ebenhoch R, Kley JT, Magarkar A, Nar H, Weichert D. Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55. Nat Commun. 2025 Feb 25;16(1):1973. PMID:40000629 doi:10.1038/s41467-025-57204-y

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9ge2

Structure of GPR55 in complex with G13 and synthetic agonist ML184

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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