8ZFZ

cryo-EM structure of Gs-coupled zebrafish GPR4 at pH 6.5

8ZFZ の概要

• エントリーDOI: 10.2210/pdb8zfz/pdb
• 関連するPDBエントリー: 8ZFJ
• EMDBエントリー: 60072
• 分子名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, scFv16, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (5 entities in total)
• 機能のキーワード: gpcr, membrane 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: 5
• 化学式量合計: 178904.22

構造登録者

Ma, Y.,Tang, M.,Ru, H.,Song, G. (登録日: 2024-05-08, 公開日: 2025-01-22, 最終更新日: 2025-07-23)

主引用文献

Ma, Y.,Wang, Y.,Tang, M.,Weng, Y.,Chen, Y.,Xu, Y.,An, S.,Wu, Y.,Zhao, S.,Xu, H.,Li, D.,Liu, M.,Lu, W.,Ru, H.,Song, G.
Cryo-EM structure of an activated GPR4-Gs signaling complex.
Nat Commun, 16:605-605, 2025

PubMed Abstract: G protein-coupled receptor 4 (GPR4) belongs to the subfamily of proton-sensing GPCRs (psGPCRs), which detect pH changes in extracellular environment and regulate diverse physiological responses. GPR4 was found to be overactivated in acidic tumor microenvironment as well as inflammation sites, with a triad of acidic residues within the transmembrane domain identified as crucial for proton sensing. However, the 3D structure remains unknown, and the roles of other conserved residues within psGPCRs are not well understood. Here we report cryo-electron microscopy (cryo-EM) structures of active zebrafish GPR4 at both pH 6.5 and 8.5, each highlighting a distribution of histidine and acidic residues at the extracellular region. Cell-based assays show that these ionizable residues moderately influence the proton-sensing capacity of zebrafish GPR4, compared to the more significant effects of the triad residues. Furthermore, we reveal a cluster of aromatic residues within the orthosteric pocket that may propagate the signaling to the intercellular region via repacking the aromatic patch at the central region. This study provides a framework for future signaling and functional investigation of psGPCRs.

PubMed: 39799123
DOI: 10.1038/s41467-025-55901-2

実験手法

ELECTRON MICROSCOPY (3.3 Å)