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<p>Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H<sub>4</sub> receptor (H<sub>4</sub>R) modulates chemotaxis and interferon production through G<sub>i</sub> protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying H<sub>4</sub>R signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the H<sub>4</sub>R-G<sub>i</sub> complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H<sub>1</sub> receptor (H<sub>1</sub>R) bound to the non-canonical G proteins G<sub>i</sub> and G<sub>s</sub>. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in H<sub>1</sub>R and H<sub>4</sub>R. Collectively, our comprehensive study revealed the structural basis for distinct mechanisms of ligand recognition and receptor activation, offering a profound insight into G protein preference across receptor subtypes.</p>

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Structural insights into ligand recognition and G protein preferences across histamine receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月27日

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  • Yuma Matsuzaki,
  • Fumiya K. Sano,
  • Hidetaka S. Oshima,
  • Hiroaki Akasaka,
  • Kazuhiro Kobayashi,
  • Tatsuki Tanaka,
  • Yuzuru Itoh,
  • Wataru Shihoya,
  • Yoshiaki Kise,
  • Tsukasa Kusakizako,
  • Asuka Inoue,
  • Osamu Nureki

摘要

Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H4 receptor (H4R) modulates chemotaxis and interferon production through Gi protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying H4R signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the H4R-Gi complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H1 receptor (H1R) bound to the non-canonical G proteins Gi and Gs. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in H1R and H4R. Collectively, our comprehensive study revealed the structural basis for distinct mechanisms of ligand recognition and receptor activation, offering a profound insight into G protein preference across receptor subtypes.