Cryo-EM structure of an activated GPR4–Gs signaling complex

Yitong Ma, Yijie Wang, Mengyuan Tang, Yuan Weng, Ying Chen, Yueming Xu, Shuxiao An, Yiran Wu, Suwen Zhao, Huanhuan Xu, Dali Li, Mingyao Liu, Weiqiang Lu (wqlu@bio.ecnu.edu.cn), Heng Ru (hengru@zju.edu.cn) and Gaojie Song (gjsong@bio.ecnu.edu.cn)
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Yitong Ma: East China Normal University
Yijie Wang: East China Normal University
Mengyuan Tang: Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University
Yuan Weng: East China Normal University
Ying Chen: East China Normal University
Yueming Xu: East China Normal University
Shuxiao An: East China Normal University
Yiran Wu: ShanghaiTech University
Suwen Zhao: ShanghaiTech University
Huanhuan Xu: Yunnan Agricultural University
Dali Li: East China Normal University
Mingyao Liu: East China Normal University
Weiqiang Lu: East China Normal University
Heng Ru: Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University
Gaojie Song: East China Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55901-2

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