9JVM

Cryo-EM structure of the receptor of xGPR4-apo in pH8.0

Summary for 9JVM

• Entry DOI: 10.2210/pdb9jvm/pdb
• EMDB information: 61840
• Descriptor: G-protein coupled receptor 4 (1 entity in total)
• Functional Keywords: ph8.0, xgpr4, receptor, membrane protein
• Biological source: Xenopus tropicalis (tropical clawed frog)
• Total number of polymer chains: 1
• Total formula weight: 38083.36

Authors

Rong, N.K.,Wen, X.,Yang, F.,Sun, J.P. (deposition date: 2024-10-09, release date: 2025-02-26)

Primary citation

Wen, X.,Shang, P.,Chen, H.,Guo, L.,Rong, N.,Jiang, X.,Li, X.,Liu, J.,Yang, G.,Zhang, J.,Zhu, K.,Meng, Q.,He, X.,Wang, Z.,Liu, Z.,Cheng, H.,Zheng, Y.,Zhang, B.,Pang, J.,Liu, Z.,Xiao, P.,Chen, Y.,Liu, L.,Luo, F.,Yu, X.,Yi, F.,Zhang, P.,Yang, F.,Deng, C.,Sun, J.P.
Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4.
Cell, 188:653-670.e24, 2025

PubMed Abstract: Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of H and H enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular H contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.

PubMed: 39753131
DOI: 10.1016/j.cell.2024.12.001

Experimental method

ELECTRON MICROSCOPY (2.36 Å)