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Title | Insights into divalent cation regulation and G-coupling of orphan receptor GPR35. |
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Journal, issue, pages | Cell Discov, Vol. 8, Issue 1, Page 135, Year 2022 |
Publish date | Dec 21, 2022 |
Authors | Jia Duan / Qiufeng Liu / Qingning Yuan / Yujie Ji / Shengnan Zhu / Yangxia Tan / Xinheng He / Youwei Xu / Jingjing Shi / Xi Cheng / Hualiang Jiang / H Eric Xu / Yi Jiang / |
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, ...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. |
External links | Cell Discov / PubMed:36543774 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.2 Å |
Structure data | EMDB-34549, PDB-8h8j: |
Chemicals | ChemComp-WYB: ChemComp-CA: ChemComp-CLR: |
Source |
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Keywords | MEMBRANE PROTEIN / GPR35 / G13 / Lodoxamide |