Structural highlights
Disease
OGR1_HUMAN Hypomaturation amelogenesis imperfecta. The disease is caused by variants affecting the gene represented in this entry.
Function
OGR1_HUMAN Proton-sensing receptor involved in pH homeostasis. May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone. Mediates its action by association with G proteins that stimulates inositol phosphate (IP) production or Ca(2+) mobilization. The receptor is almost silent at pH 7.8 but fully activated at pH 6.8. Also functions as a metastasis suppressor gene in prostate cancer (By similarity).[1]
Publication Abstract from PubMed
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 approximately 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.
, PMID:39753132[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. Proton-sensing G-protein-coupled receptors. Nature. 2003 Sep 4;425(6953):93-8. PMID:12955148 doi:10.1038/nature01905
- ↑ Howard MK, Hoppe N, Huang XP, Mitrovic D, Billesbølle CB, Macdonald CB, Mehrotra E, Rockefeller Grimes P, Trinidad DD, Delemotte L, English JG, Coyote-Maestas W, Manglik A. Molecular basis of proton sensing by G protein-coupled receptors. Cell. 2024 Dec 26:S0092-8674(24)01373-4. PMID:39753132 doi:10.1016/j.cell.2024.11.036
