Matsuzaki Yuma, Sano Fumiya K, Oshima Hidetaka S, Akasaka Hiroaki, Kobayashi Kazuhiro, Tanaka Tatsuki, Itoh Yuzuru, Shihoya Wataru, Kise Yoshiaki, Kusakizako Tsukasa, Inoue Asuka, Nureki Osamu
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan.
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo, Japan.
Commun Biol. 2025 Jun 27;8(1):957. doi: 10.1038/s42003-025-08363-7.
Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H receptor (HR) modulates chemotaxis and interferon production through G protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying HR signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the HR-G complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H receptor (HR) bound to the non-canonical G proteins G and G. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in HR and HR. 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.
组胺通过激活四种受体亚型发挥关键的生理作用，每种亚型都表现出对特定G蛋白的偏好。其中，组胺H受体（HR）通过G蛋白激活调节趋化性和干扰素产生，表明其具有治疗潜力。尽管其具有生理意义，但组胺受体间HR信号传导及G蛋白偏好的潜在机制仍知之甚少。在此，我们展示了HR-G复合物的冷冻电镜结构，揭示了组胺识别和受体激活的独特机制。我们还解析了与非经典G蛋白G和G结合的组胺H受体（HR）的结构。通过功能分析和计算分析相结合，我们确定细胞内环2是HR和HR中G蛋白偏好的关键决定因素。总体而言，我们的综合研究揭示了配体识别和受体激活不同机制的结构基础，为深入了解受体亚型间的G蛋白偏好提供了深刻见解。
