Journal
CELL DISCOVERY
Volume 8, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41421-022-00499-8
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Funding
- National Natural Science Foundation [32171187, 82121005, 32130022, 81902085, 81903433]
- Ministry of Science and Technology (China) [2018YFA0507002]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- CAS Strategic Priority Research Program [XDB37030103]
- Shanghai Sailing Program [19YF1457600]
- Key Tasks of LG Laboratory [LG202101-01-03]
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This study reports the cryo-electron microscopy structure of GPR35 coupled with G(13) and bound to the anti-allergic drug lodoxamide. The structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35, providing insights into its ligand binding promiscuity. Structural comparison with other G protein subtypes-coupled GPCRs highlights significant movements in the G alpha(13) subunit and the GPR35 TM6 helix.
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 alpha 5 helix of the G alpha(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.
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