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Structural basis and biased signaling of proton sensation by GPCRs mediated by extracellular histidine rearrangement.

Lu Guo,Kongkai Zhu,Ya-Ni Zhong,Mingxin Gao,Junyan Liu,Zhimin Qi,Zili Liu,Naikang Rong,Minghui Zhang,Dongfang Li,Qi-Yue Zhang,Gongming Yang,Xinxin Zhang,Ming-yue Zhang,Ning Ding,Yu-Qi Ping,Zhao Yang,Peng Xiao,Ming Xia,Xiao Yu,Alatan Gaole,Jin-Peng Sun,Fan Yang

Published 2025 in Molecules and Cells

ABSTRACT

Proton sensing by G protein-coupled receptors (GPCRs) is crucial in many life activities. However, its underlying mechanism remains unclear. Here, we report 8 cryoelectron microscopy (cryo-EM) structures of human GPR4 and GPR68 at different pH values and in complex with Gs or Gq trimers or in apo state. Structural inspection, structure-based pKa calculations, and mutational and computational analyses revealed that protonation of two conserved extracellular histidines induced polar network formation and other conformational changes to tether 7-transmembrane (TM7) to second extracellular loop (ECL2), and these changes constitute the central mechanisms of proton-induced activation of GPR4 and GPR68. Unexpectedly, proton sensation by specific extracellular histidine determined biased G protein coupling of GPR4. Moreover, GPR68's additional pH-sensing H842.67 enhances its function in a more acidic optimal pH range. The propagation path connecting proton-sensing histidines to the toggle switch was characterized. Collectively, we provide structural insights into the proton sensing, activation, and downstream effector coupling mechanisms of proton-sensing GPCRs.

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