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<p>GPR99 holds promise as a potential therapeutic target for inflammatory diseases. GPR99 exhibits marked basal activity when coupled with the G<sub>q</sub> protein, its activation mechanism remains elusive. In this study, we determine the high-resolution structure of the human GPR99 in complex with the heterotrimeric miniG<sub>q</sub> in the ligand-free state using cryo-electron microscopy (cryo-EM). Our structural analysis and functional experiments reveal that the second extracellular loop (ECL2) of GPR99 occupies the orthosteric binding pocket, thereby promoting receptor self-activation. Moreover, we observe structural water molecules forming an extended polar network that connects ECL2 and the binding pocket, intricately linking these elements to the receptor’s functional activity. Structure-based mutagenesis experiments further validate the critical role of ECL2 in intracellular signal transduction of GPR99, offering a structural basis for exploring its function under physiological or pathological conditions. Additionally, these findings also provide a crucial theoretical framework for the design of drugs targeting GPR99.</p>

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Structural analysis reveals that water molecules mediate self-activation of GPR99

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Miaofang Xiao,
  • Xiaoling Bao,
  • Yusheng Guo,
  • Jiawei Li,
  • Tiancai Chang,
  • Fumei Zhong,
  • Xiaomin Mao,
  • Mu Li,
  • Siqi Liu,
  • Wanbiao Chen,
  • Limin Zhao,
  • Chongyuan Wang,
  • Heng Liu

摘要

GPR99 holds promise as a potential therapeutic target for inflammatory diseases. GPR99 exhibits marked basal activity when coupled with the Gq protein, its activation mechanism remains elusive. In this study, we determine the high-resolution structure of the human GPR99 in complex with the heterotrimeric miniGq in the ligand-free state using cryo-electron microscopy (cryo-EM). Our structural analysis and functional experiments reveal that the second extracellular loop (ECL2) of GPR99 occupies the orthosteric binding pocket, thereby promoting receptor self-activation. Moreover, we observe structural water molecules forming an extended polar network that connects ECL2 and the binding pocket, intricately linking these elements to the receptor’s functional activity. Structure-based mutagenesis experiments further validate the critical role of ECL2 in intracellular signal transduction of GPR99, offering a structural basis for exploring its function under physiological or pathological conditions. Additionally, these findings also provide a crucial theoretical framework for the design of drugs targeting GPR99.