8H8J

Lodoxamide-bound GPR35 in complex with G13

Summary for 8H8J

• Entry DOI: 10.2210/pdb8h8j/pdb
• EMDB information: 34549
• Descriptor: Guanine nucleotide-binding protein subunit alpha-13, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, G-protein coupled receptor 35, ... (8 entities in total)
• Functional Keywords: gpr35, g13, lodoxamide, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 152272.79

Authors

Yuan, Q.,Duan, J.,Liu, Q.,Xu, H.E.,Jiang, Y. (deposition date: 2022-10-23, release date: 2023-02-08, Last modification date: 2024-10-23)

Primary citation

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, 8:135-135, 2022

PubMed Abstract: 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, G, and G, insufficient structural evidence is accessible to understand the coupling mechanism of G 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 coupling. Here we report a cryo-electron microscopy structure of G-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 complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of α5 helix of the Gα 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 coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.

PubMed: 36543774
DOI: 10.1038/s41421-022-00499-8

Experimental method

ELECTRON MICROSCOPY (3.2 Å)