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TitleMolecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.
Journal, issue, pagesCell Discov, Vol. 11, Issue 1, Page 59, Year 2025
Publish dateJun 25, 2025
AuthorsChongzhao You / Shimeng Guo / Tianwei Zhang / Xinheng He / Tianyu Gao / Wenwen Xin / Zining Zhu / Yujie Lu / Youwei Xu / Zhen Li / Yumu Zhang / Xi Cheng / Yi Jiang / Xin Xie / H Eric Xu /
PubMed AbstractMaintaining 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 ...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.
External linksCell Discov / PubMed:40555728 / PubMed Central
MethodsEM (single particle)
Resolution2.36 - 2.59 Å
Structure data

61370

9jco

EMDB-61370, PDB-9jco:
Cryo-EM structure of the proton-sensing GPCR (GPR4)-Gs protein complex at pH 6.5
Method: EM (single particle) / Resolution: 2.36 Å

61371

9jcp

EMDB-61371, PDB-9jcp:
Cryo-EM structure of the proton-sensing GPCR (GPR4)-Gq protein complex at pH 7.4
Method: EM (single particle) / Resolution: 2.55 Å

61372

9jcq

EMDB-61372, PDB-9jcq:
Cryo-EM structure of the proton-sensing GPCR (GPR4)-Gs protein complex at pH 7.4
Method: EM (single particle) / Resolution: 2.59 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

PDB-1l35:
STRUCTURE OF A THERMOSTABLE DISULFIDE-BRIDGE MUTANT OF PHAGE T4 LYSOZYME SHOWS THAT AN ENGINEERED CROSSLINK IN A FLEXIBLE REGION DOES NOT INCREASE THE RIGIDITY OF THE FOLDED PROTEIN

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsSIGNALING PROTEIN / Cryo-EM / GPCR / proton-sensing / GPR4 / pH 6.5 / Gs / complex / pH 7.4 / Gq

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