9BHM

Human proton sensing receptor GPR68 in complex with miniGs

9BHM の概要

• エントリーDOI: 10.2210/pdb9bhm/pdb
• EMDBエントリー: 44550
• 分子名称: Ovarian cancer G-protein coupled receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• 機能のキーワード: receptor, proton-sensor, g protein, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129252.15

構造登録者

Howard, M.K.,Hoppe, N.,Huang, X.P.,Macdonald, C.B.,Mehrotra, E.,Rockefeller Grimes, P.,Zahm, A.M.,Trinidad, D.D.,English, J.,Coyote-Maestas, W.,Manglik, A. (登録日: 2024-04-21, 公開日: 2025-01-22, 最終更新日: 2025-02-19)

主引用文献

Howard, M.K.,Hoppe, N.,Huang, X.P.,Mitrovic, D.,Billesbolle, C.B.,Macdonald, C.B.,Mehrotra, E.,Rockefeller Grimes, P.,Trinidad, D.D.,Delemotte, L.,English, J.G.,Coyote-Maestas, W.,Manglik, A.
Molecular basis of proton sensing by G protein-coupled receptors.
Cell, 188:671-, 2025

PubMed 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.

PubMed: 39753132
DOI: 10.1016/j.cell.2024.11.036

実験手法

ELECTRON MICROSCOPY (2.9 Å)