Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35

doi:10.1038/s41421-022-00499-8

	Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35
	Duan, Jia 1,2; Liu, Qiufeng 1; Yuan, Qingning 1; Ji, Yujie 1,2; Zhu, Shengnan 3; Tan, Yangxia 1; He, Xinheng 1,2; Xu, Youwei 1; Shi, Jingjing 1; Cheng, Xi 1,2,4; Jiang, Hualiang1,2,4,5,6 ; Eric Xu, H.1,2,5,6 ; Jiang, Yi1,2,5,7
	2022-12-21
发表期刊	CELL DISCOVERY (IF:13.0[JCR-2023],14.8[5-Year])
EISSN	2056-5968
卷号	8 期号:1
发表状态	已发表
DOI	10.1038/s41421-022-00499-8
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.
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收录类别	SCI
语种	英语
资助项目	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]
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000901867400001
出版者	SPRINGERNATURE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/272811
专题	生命科学与技术学院_特聘教授组_徐华强组生命科学与技术学院免疫化学研究所_特聘教授组_蒋华良组
通讯作者	Eric Xu, H.; Jiang, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Macau Univ Sci & Technol, Sch Pharm, Macau, Peoples R China 4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Zhejiang, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 7.Lingang Lab, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
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).
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).
MLA	Duan, Jia,et al."Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35".CELL DISCOVERY 8.1(2022).