8h8j

Lodoxamide-bound GPR35 in complex with G13Lodoxamide-bound GPR35 in complex with G13

Structural highlights

8h8j is a 5 chain structure with sequence from 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 3.2Å
Ligands:	, ,
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

Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes G(s), G(i/o), and G(q/11), insufficient structural evidence is accessible to understand the coupling mechanism of G(12/13) protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel diseases (IBDs), stands out as a prototypical receptor for investigating ionic modulation and G(13) coupling. Here we report a cryo-electron microscopy structure of G(13)-coupled GPR35 bound to an anti-allergic drug, lodoxamide. This structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35 and also presents a highly positively charged binding pocket and the complementary electrostatic ligand recognition mode, which explain the promiscuity of acidic ligand binding by GPR35. Structural comparison of the GPR35-G(13) complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of alpha5 helix of the Galpha(13) subunit towards the receptor core and the least outward displacement of the cytoplasmic end of GPR35 TM6. A featured 'methionine pocket' contributes to the G(13) coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G(13) protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.

Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35.,Duan J, Liu Q, Yuan Q, Ji Y, Zhu S, Tan Y, He X, Xu Y, Shi J, Cheng X, Jiang H, Eric Xu H, Jiang Y Cell Discov. 2022 Dec 21;8(1):135. doi: 10.1038/s41421-022-00499-8. PMID:36543774^[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
↑ Duan J, Liu Q, Yuan Q, Ji Y, Zhu S, Tan Y, He X, Xu Y, Shi J, Cheng X, Jiang H, Eric Xu H, Jiang Y. Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35. Cell Discov. 2022 Dec 21;8(1):135. PMID:36543774 doi:10.1038/s41421-022-00499-8

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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] Duan J, Liu Q, Yuan Q, Ji Y, Zhu S, Tan Y, He X, Xu Y, Shi J, Cheng X, Jiang H, Eric Xu H, Jiang Y. Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35. Cell Discov. 2022 Dec 21;8(1):135. PMID:36543774 doi:10.1038/s41421-022-00499-8

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