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作者

Lulu Guo Kongkai Zhu Ya-Ni Zhong Mingxin Gao Junyan Liu Zhimin Qi Zili Liu Naikang Rong Minghui Zhang Dongfang Li Qiyue Zhang Gongming Yang Xinxin Zhang Mingyue Zhang Ning Ding Yu-qi Ping Zhao Yang Peng Xiao Ming Xia Xiao Yu

作者单位

¹²Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China ⁵Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China ¹Advanced Medical Research Institute, Cheeloo College of Medicine, The Second Hospital Shandong University, Jinan, China ⁹Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China ⁷Department of Orthopaedics, The Third Xiangya Hospital, Central South University, Changsha 410013, China ⁴State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine ⁸School of Life Sciences, Inner Mongolia University, Hohhot, China ¹⁰Department of Anesthesiology, Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China ²These authors contributed equally ³Beijing Key Laboratory of Cardiovascular Receptors Research ¹¹Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China ⁶Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, China

刊名

Molecular Cell

年份

2025

ISSN

1097-2765

摘要

Proton sensing by G protein-coupled receptors is crucial in many life activities. However, its underlying mechanism remains unclear. Here, we report 8 cryoelectron microscopy 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 co...更多

Proton sensing by G protein-coupled receptors is crucial in many life activities. However, its underlying mechanism remains unclear. Here, we report 8 cryoelectron microscopy 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 to second extracellular loop , 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 H84 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.收起

文献类型

期刊