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Structure paper

TitleMolecular basis of proton sensing by G protein-coupled receptors.
Journal, issue, pagesCell, Vol. 188, Issue 3, Page 671-687.e20, Year 2025
Publish dateFeb 6, 2025
AuthorsMatthew K Howard / Nicholas Hoppe / Xi-Ping Huang / Darko Mitrovic / Christian B Billesbølle / Christian B Macdonald / Eshan Mehrotra / Patrick Rockefeller Grimes / Donovan D Trinidad / Lucie Delemotte / Justin G English / Willow Coyote-Maestas / Aashish Manglik /
PubMed AbstractThree proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. ...Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.
External linksCell / PubMed:39753132 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.0 Å
Structure data

EMDB-44548: Human proton sensing receptor GPR65 in complex with miniGs - focused map of 7TM
Method: EM (single particle) / Resolution: 3.0 Å

44549

9bhl

EMDB-44549, PDB-9bhl:
Human proton sensing receptor GPR65 in complex with miniGs
Method: EM (single particle) / Resolution: 2.8 Å

44550

9bhm

EMDB-44550, PDB-9bhm:
Human proton sensing receptor GPR68 in complex with miniGs
Method: EM (single particle) / Resolution: 2.9 Å

44560

9bi6

EMDB-44560, PDB-9bi6:
Human proton sensing receptor GPR68 in complex with miniGsq
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-44561: Human proton sensing receptor GPR68 in complex with miniGsq - focused map of 7TM
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-44596: Human proton sensing receptor GPR4 in complex with miniGs - focused map of 7TM
Method: EM (single particle) / Resolution: 3.0 Å

44597

9bip

EMDB-44597, PDB-9bip:
Human proton sensing receptor GPR4 in complex with miniGs
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN / Receptor / Proton-sensor / G protein

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