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TitleStructural basis of stepwise proton sensing-mediated GPCR activation.
Journal, issue, pagesCell Res, Vol. 35, Issue 6, Page 423-436, Year 2025
Publish dateApr 11, 2025
AuthorsXiaolei Yue / Li Peng / Shenhui Liu / Bingjie Zhang / Xiaodan Zhang / Hao Chang / Yuan Pei / Xiaoting Li / Junlin Liu / Wenqing Shui / Lijie Wu / Huji Xu / Zhi-Jie Liu / Tian Hua /
PubMed AbstractThe regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 ...The regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 and GPR68, play a pivotal role in detecting changes in extracellular proton concentrations, impacting both physiological and pathological states. However, comprehensive understanding of the proton sensing mechanism is still elusive. Here, we determined the cryo-electron microscopy structures of GPR4 and GPR65 in various activation states across different pH levels, coupled with G, G or G proteins, as well as a small molecule NE52-QQ57-bound inactive GPR4 structure. These structures reveal the dynamic nature of the extracellular loop 2 and its signature conformations in different receptor states, and disclose the proton sensing mechanism mediated by networks of extracellular histidine and carboxylic acid residues. Notably, we unexpectedly captured partially active intermediate states of both GPR4-G and GPR4-G complexes, and identified a unique allosteric binding site for NE52-QQ57 in GPR4. By integrating prior investigations with our structural analysis and mutagenesis data, we propose a detailed atomic model for stepwise proton sensation and GPCR activation. These insights may pave the way for the development of selective ligands and targeted therapeutic interventions for pH sensing-relevant diseases.
External linksCell Res / PubMed:40211064 / PubMed Central
MethodsEM (single particle)
Resolution2.67 - 3.35 Å
Structure data

39927

8zce

EMDB-39927, PDB-8zce:
Cryo-EM structure of GPR4 complexed with Gs in pH6.0
Method: EM (single particle) / Resolution: 3.1 Å

39928

8zcf

EMDB-39928, PDB-8zcf:
Cryo-EM structure of GPR4 complexed with Gs in pH7.5
Method: EM (single particle) / Resolution: 2.9 Å

61439

9jft

EMDB-61439, PDB-9jft:
Cryo-EM structure of GPR65 complexed with miniGs in pH6.5
Method: EM (single particle) / Resolution: 3.27 Å

61440

9jfu

EMDB-61440, PDB-9jfu:
Cryo-EM structure of inactive GPR4 with NE52-QQ57
Method: EM (single particle) / Resolution: 3.23 Å

61441

9jfv

EMDB-61441, PDB-9jfv:
Cryo-EM structure of GPR4 complexed with miniGs/q in pH6.8
Method: EM (single particle) / Resolution: 2.67 Å

61442

9jfw

EMDB-61442, PDB-9jfw:
Cryo-EM structure of GPR4 complexed with Gs in pH6.8
Method: EM (single particle) / Resolution: 3.13 Å

61443

9jfx

EMDB-61443, PDB-9jfx:
Cryo-EM structure of GPR4 complexed with miniGs/q in pH7.5
Method: EM (single particle) / Resolution: 2.87 Å

61445

9jfz

EMDB-61445, PDB-9jfz:
Cryo-EM structure of intermediate state GPR4 complexed with miniGs/q in pH7.5
Method: EM (single particle) / Resolution: 2.9 Å

61489

9jhp

EMDB-61489, PDB-9jhp:
Cryo-EM structure of GPR4 complexed with miniG13 in pH6.8
Method: EM (single particle) / Resolution: 3.35 Å

63068

9lgm

EMDB-63068, PDB-9lgm:
Cryo-EM structure of GPR4 complexed with Gs in pH8.0
Method: EM (single particle) / Resolution: 2.84 Å

Chemicals

PDB-1l1e:
Crystal Structure of Mycolic Acid Cyclopropane Synthase PcaA Complexed with S-adenosyl-L-homocysteine

Source
  • homo sapiens (human)
  • lama glama (llama)
  • Escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / GPR4 / DNGs / Proton sensing / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex / GPR65 / miniGs / Gs / Gsq / G Protein / miniG13

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