Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35
文献类型：期刊论文
| 作者 | Duan, Jia3,4; Liu, Qiufeng3; Yuan, Qingning3; Ji, Yujie3,4; Zhu, Shengnan5; Tan, Yangxia3; He, Xinheng3,4; Xu, Youwei3; Shi, Jingjing3 ; Cheng, Xi3,4,6
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| 刊名 | CELL DISCOVERY
 |
| 出版日期 | 2022-12-21 |
| 卷号 | 8期号:1页码:12 |
| DOI | 10.1038/s41421-022-00499-8 |
| 通讯作者 | Eric Xu, H.(eric.xu@simm.ac.cn) ; Jiang, Yi(yjiang@lglab.ac.cn) |
| 英文摘要 | 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. |
| WOS关键词 | KYNURENIC ACID ; BINDING-SITES ; MAGNESIUM ; LIGAND ; LOCI ; ACTIVATION ; AGONIST ; DISEASE ; GPCRS ; RISK |
| 资助项目 | National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[81902085] ; National Natural Science Foundation[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] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| 出版者 | SPRINGERNATURE |
| WOS记录号 | WOS:000901867400001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/303902]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Eric Xu, H.; Jiang, Yi |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Lingang Lab, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Macau Univ Sci & Technol, Sch Pharm, Macau, Peoples R China 6.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Zhejiang, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Duan, Jia,Liu, Qiufeng,Yuan, Qingning,et al. Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35[J]. CELL DISCOVERY,2022,8(1):12. |
| APA | Duan, Jia.,Liu, Qiufeng.,Yuan, Qingning.,Ji, Yujie.,Zhu, Shengnan.,...&Jiang, Yi.(2022).Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35.CELL DISCOVERY,8(1),12. |
| MLA | Duan, Jia,et al."Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35".CELL DISCOVERY 8.1(2022):12. |
入库方式： OAI收割
来源：上海药物研究所
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