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Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling

文献类型：期刊论文

作者You, Chongzhao6,7; Guo, Shimeng7; Zhang, Tianwei4,5; He, Xinheng6,7; Gao, Tianyu5; Xin, Wenwen3,6,7; Zhu, Zining2; Lu, Yujie2,7; Xu, Youwei6,7; Li, Zhen2,7
刊名CELL DISCOVERY
出版日期2025-06-25
卷号11期号:1页码:11
DOI10.1038/s41421-025-00807-y
英文摘要Maintaining pH homeostasis is critical for cellular function across all living organisms. Proton-sensing G protein-coupled receptors (GPCRs), particularly GPR4, play a pivotal role in cellular responses to pH changes. Yet, the molecular mechanisms underlying their proton sensing and activation remain incompletely understood. Here we present high-resolution cryo-electron microscopy structures of GPR4 in complex with G proteins under physiological and acidic pH conditions. Our structures reveal an intricate proton-sensing mechanism driven by a sophisticated histidine network in the receptor's extracellular domain. Upon protonation of key histidines under acidic conditions, a remarkable conformational cascade is initiated, propagating from the extracellular region to the intracellular G protein-coupling interface. This dynamic process involves precise transmembrane helix rearrangements and conformational shifts of conserved motifs, mediated by strategically positioned water molecules. Notably, we discovered a bound bioactive lipid, lysophosphatidylcholine, which has positive allosteric effects on GPR4 activation. These findings provide a comprehensive framework for understanding proton sensing in GPCRs and the interplay between pH sensing and lipid regulation, offering insights into cellular pH homeostasis and potential therapies for pH-related disorders.
WOS关键词PROTEIN-COUPLED RECEPTORS ; ALLOSTERIC REGULATION ; ACID ; HISTIDINE ; LYSOPHOSPHATIDYLCHOLINE ; INFLAMMATION ; ATPASE ; TDAG8
资助项目National Natural Science Foundation of China (National Science Foundation of China)[82121005] ; National Natural Science Foundation of China (National Science Foundation of China)[32130022] ; National Natural Science Foundation of China (National Science Foundation of China)[82330113] ; National Natural Science Foundation of China (National Science Foundation of China)[82304579] ; National Natural Science Foundation of China (National Science Foundation of China)[32171187] ; National Natural Science Foundation of China[2019SHZDZX02] ; Shanghai Municipal Science and Technology Commission Major Project[XDB37030103] ; Shanghai Municipal Science and Technology Commission Major Project[LG-GG-202204-01] ; CAS Strategic Priority Research Program[2022684] ; Shanghai Post-doctoral Excellence Program
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001514417000001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/318492]  
专题新药研究国家重点实验室
通讯作者You, Chongzhao; Jiang, Yi; Xie, Xin; Xu, H. Eric
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Shandong, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Jiangsu, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Zhejiang, Peoples R China
4.Lingang Lab, Shanghai, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Beijing, 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		 You, Chongzhao,Guo, Shimeng,Zhang, Tianwei,et al. Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling[J]. CELL DISCOVERY,2025,11(1):11.
APA You, Chongzhao.,Guo, Shimeng.,Zhang, Tianwei.,He, Xinheng.,Gao, Tianyu.,...&Xu, H. Eric.(2025).Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.CELL DISCOVERY,11(1),11.
MLA You, Chongzhao,et al."Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling".CELL DISCOVERY 11.1(2025):11.

入库方式： OAI收割

来源：上海药物研究所

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