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© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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.

Details

Title
Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling
Author
You, Chongzhao 1   VIAFID ORCID Logo  ; Guo, Shimeng 2   VIAFID ORCID Logo  ; Zhang, Tianwei 3   VIAFID ORCID Logo  ; He, Xinheng 1   VIAFID ORCID Logo  ; Gao, Tianyu 4 ; Xin, Wenwen 5 ; Zhu, Zining 6 ; Lu, Yujie 7 ; Xu, Youwei 1   VIAFID ORCID Logo  ; Li, Zhen 7 ; Zhang, Yumu 4 ; Cheng, Xi 5   VIAFID ORCID Logo  ; Jiang, Yi 3   VIAFID ORCID Logo  ; Xie, Xin 8   VIAFID ORCID Logo  ; Xu, H. Eric 9   VIAFID ORCID Logo 

 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
 ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Lingang Laboratory, Shanghai, China (GRID:grid.440637.2) 
 ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879) 
 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419); University of Chinese Academy of Sciences, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, Hangzhou, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
 Nanjing University of Chinese Medicine, School of Chinese Materia Medica, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045) 
 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); Nanjing University of Chinese Medicine, School of Chinese Materia Medica, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045) 
 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, Hangzhou, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419); Nanjing University of Chinese Medicine, School of Chinese Materia Medica, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045); Bohai Rim Advanced Research Institute for Drug Discovery, Shandong Laboratory of Yantai Drug Discovery, Yantai, China (GRID:grid.410745.3) 
 Chinese Academy of Sciences, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419); ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Lingang Laboratory, Shanghai, China (GRID:grid.440637.2); Nanjing University of Chinese Medicine, School of Chinese Materia Medica, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045) 
Pages
59
Publication year
2025
Publication date
2025
Publisher
Springer Nature B.V.
e-ISSN
20565968
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3226332944
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.