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-Structure paper
タイトル | Insights into divalent cation regulation and G-coupling of orphan receptor GPR35. |
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ジャーナル・号・ページ | Cell Discov, Vol. 8, Issue 1, Page 135, Year 2022 |
掲載日 | 2022年12月21日 |
著者 | 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 要旨 | 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. |
リンク | Cell Discov / PubMed:36543774 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.2 Å |
構造データ | EMDB-34549, PDB-8h8j: |
化合物 | ChemComp-WYB: ChemComp-CA: ChemComp-CLR: |
由来 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / GPR35 / G13 / Lodoxamide |