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Structural basis of stepwise proton sensing-mediated GPCR activation
Xiaolei Yue1,2, Li Peng1,2, Shenhui Liu1,2
1iHuman Institute, ShanghaiTech University, Shanghai, China.
Cell Research
|April 10, 2025
Summary
This study reveals the structural mechanisms of pH-sensing G protein-coupled receptors (GPCRs), like GPR4 and GPR65, detailing how they detect acidity and activate. These findings offer new therapeutic targets for pH-related diseases.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Pharmacology
Background:
- pH homeostasis is critical for biological functions.
- pH-sensing G protein-coupled receptors (GPCRs) like GPR4, GPR65, and GPR68 are key regulators of cellular pH.
- The precise proton sensing mechanism of these GPCRs remains largely unknown.
Purpose of the Study:
- To elucidate the structural basis of proton sensing and activation mechanisms in GPR4 and GPR65.
- To understand the role of extracellular loops and specific residues in pH detection.
- To provide atomic-level insights into GPCR activation triggered by pH changes.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine structures of GPR4 and GPR65.
- Structural analysis of receptors in complex with Gs, Gq, or G13 proteins across various pH levels.
- Co-crystallization of GPR4 with a small molecule NE52-QQ57.
Main Results:
- Detailed structures of GPR4 and GPR65 reveal dynamic extracellular loop 2 conformations.
- Proton sensing mechanism elucidated through networks of extracellular histidine and carboxylic acid residues.
- Identification of partially active intermediate states and a unique allosteric NE52-QQ57 binding site on GPR4.
Conclusions:
- A comprehensive atomic model for stepwise proton sensation and GPCR activation is proposed.
- Structural insights provide a foundation for developing novel therapeutics targeting pH-sensing GPCRs.
- Understanding these mechanisms is crucial for treating diseases associated with aberrant pH sensing.
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