ヒスタミン受容体のGタンパク質選択性の分子機構を解明

2025-06-27 東京大学

H₁R/H₄R と各Gタンパク質との相互作用の模式図

<関連情報>

• https://www.s.u-tokyo.ac.jp/ja/press/10837/
• https://www.nature.com/articles/s42003-025-08363-7

ヒスタミン受容体におけるリガンド認識とGタンパク質選択性に関する構造的洞察 Structural insights into ligand recognition and G protein preferences across histamine receptors

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
Communications Biology  Published:27 June 2025
DOI:https://doi.org/10.1038/s42003-025-08363-7

Abstract

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 G_i 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-G_i 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 G_i and G_s. 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.