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Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119

文献类型：期刊论文

作者Xu, Peiyu2,9; Huang, Sijie1,9; Guo, Shimeng9; Yun, Ying8; Cheng, Xi9; He, Xinheng7,9; Cai, Pengjun9; Lan, Yuan6; Zhou, Hu9; Jiang, Hualiang4,5,7,8,9
刊名NATURE STRUCTURAL & MOLECULAR BIOLOGY
出版日期2022-08-15
页码29
ISSN号1545-9993
DOI10.1038/s41594-022-00816-5
通讯作者Jiang, Yi(yjiang@lglab.ac.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要Lysophosphatidylcholine (LPC) is an essential mediator in human lipid metabolism and is associated with a variety of diseases, but the exact identity of LPC receptors remains controversial. Through extensive biochemical and structural analyses, we have identified the orphan receptor GPR119 as the receptor for LPC. The structure of the GPR119-G-protein complex without any added ligands reveals a density map that fits well with LPC, which is further confirmed by mass spectrometry and functional studies. As LPCs are abundant on the cell membrane, their preoccupancy in the receptor may lead to 'constitutive activity' of GPR119. The structure of GPR119 bound to APD668, a clinical drug candidate for type 2 diabetes, reveals an exceedingly similar binding mode to LPC. Together, these data highlight structural evidence for LPC function in regulating glucose-dependent insulin secretion through direct binding and activation of GPR119, and provide structural templates for drug design targeting GPR119. The cryo-EM structures reveal orphan receptor GPR119 as the receptor for LPC. The structures with biochemical and functional data highlight evidence for LPC function in glucose regulation, and provide templates for drug design targeting GPR119.
WOS关键词GLUCAGON-LIKE PEPTIDE-1 ; CRYO-EM STRUCTURE ; CRYSTAL-STRUCTURE ; INSULIN-SECRETION ; GLYCEMIC CONTROL ; ANALOGS ; TARGET
资助项目Ministry of Science and Technology (China) grant[2018YFA0507002] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[81730099] ; National Natural Science Foundation[32171187] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Projects[2019SHZDZX02] ; Shanghai Municipal Science and Technology Major Projects[TM202101H005] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
语种英语
WOS记录号WOS:000840587700001
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/302281]  
专题新药研究国家重点实验室
通讯作者Jiang, Yi; Xie, Xin; Xu, H. Eric
作者单位1.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA
2.MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Lingang Lab, Shanghai, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
7.Univ Chinese Acad Sci, Beijing, Peoples R China
8.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Peiyu,Huang, Sijie,Guo, Shimeng,et al. Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY,2022:29.
APA Xu, Peiyu.,Huang, Sijie.,Guo, Shimeng.,Yun, Ying.,Cheng, Xi.,...&Xu, H. Eric.(2022).Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119.NATURE STRUCTURAL & MOLECULAR BIOLOGY,29.
MLA Xu, Peiyu,et al."Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119".NATURE STRUCTURAL & MOLECULAR BIOLOGY (2022):29.

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来源：上海药物研究所

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