Structural insights into ligand recognition and G protein preferences across histamine receptors
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.
Authors
- Hiroaki Akasaka (ORCID: https://orcid.org/0000-0003-2118-0912)
- Tsukasa Kusakizako (ORCID: https://orcid.org/0000-0002-6186-6647)
- Osamu Nureki (ORCID: https://orcid.org/0000-0003-1813-7008)
- Yuma Matsuzaki (ORCID: https://orcid.org/0000-0003-2545-233X)
- Yoshiaki Kise (ORCID: https://orcid.org/0000-0002-1840-5028)
- Yuzuru Itoh (ORCID: https://orcid.org/0000-0001-7802-5572)
- Hidetaka S. Oshima (ORCID: https://orcid.org/0009-0000-0341-707X)
- Wataru Shihoya (ORCID: https://orcid.org/0000-0003-4813-5740)
- Tatsuki Tanaka (ORCID: https://orcid.org/0000-0001-5728-7573)
- Fumiya K. Sano (ORCID: https://orcid.org/0000-0002-8965-788X)
- Asuka Inoue (ORCID: https://orcid.org/0000-0003-0805-4049)
- Kazuhiro Kobayashi (ORCID: https://orcid.org/0000-0002-3366-3586)
Institutions
- Tohoku University (JP)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- The University of Tokyo (JP)
- Tohoku Medical and Pharmaceutical University (JP)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1038/s42003-025-08363-7
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- University of Tokyo
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Precursory Research for Embryonic Science and Technology