9bhm

Human proton sensing receptor GPR68 in complex with miniGsHuman proton sensing receptor GPR68 in complex with miniGs

Structural highlights 9bhm is a 4 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.9Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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). 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. Molecular basis of proton sensing by G protein-coupled receptors.,Howard MK, Hoppe N, Huang XP, Mitrovic D, Billesbolle CB, Macdonald CB, Mehrotra E, Rockefeller Grimes P, Trinidad DD, Delemotte L, English JG, Coyote-Maestas W, Manglik A Cell. 2024 Dec 26:S0092-8674(24)01373-4. doi: 10.1016/j.cell.2024.11.036. PMID:39753132 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 9bhm, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image