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-Structure paper
| タイトル | Molecular basis of proton sensing by G protein-coupled receptors. |
|---|---|
| ジャーナル・号・ページ | Cell, Vol. 188, Issue 3, Page 671-687.e20, Year 2025 |
| 掲載日 | 2025年2月6日 |
著者 | Matthew 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 要旨 | 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. ...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. |
リンク | Cell / PubMed:39753132 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 2.8 - 3.0 Å |
| 構造データ | ![]() EMDB-44548: Human proton sensing receptor GPR65 in complex with miniGs - focused map of 7TM EMDB-44549, PDB-9bhl: EMDB-44550, PDB-9bhm: EMDB-44560, PDB-9bi6: ![]() EMDB-44561: Human proton sensing receptor GPR68 in complex with miniGsq - focused map of 7TM ![]() EMDB-44596: Human proton sensing receptor GPR4 in complex with miniGs - focused map of 7TM EMDB-44597, PDB-9bip: |
| 化合物 | ![]() ChemComp-Y01: |
| 由来 |
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キーワード | SIGNALING PROTEIN / Receptor / Proton-sensor / G protein |
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