EMD-44550

Single-particle
2.9 Å
EMD-44550 Deposition: 21/04/2024
Map released: 22/01/2025
Last modified: 22/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-44550

Human proton sensing receptor GPR68 in complex with miniGs

EMD-44550

Single-particle
2.9 Å
EMD-44550 Deposition: 21/04/2024
Map released: 22/01/2025
Last modified: 22/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Lama glama
Sample: Complex of GPR68 bound to Gs heterotrimer
Fitted models: 9bhm (Avg. Q-score: 0.456)

Deposition Authors: Howard MK, Hoppe N, Huang XP, Macdonald CB , Mehrotra E, Rockefeller Grimes P, Zahm AM, Trinidad DD, English J, Coyote-Maestas W, Manglik A
Molecular basis of proton sensing by G protein-coupled receptors.
PUBMED: 39753132
DOI: doi:10.1016/j.cell.2024.11.036
ISSN: 1097-4172
Abstract:
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.