Structural basis of ligand recognition and activation of the histamine receptor family
Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and neurotransmission. Here, we determine 9 cryo-electron microscopy (cryo-EM) structures of the 4 histamine receptors in complex with four different G protein subtypes, with endogenous or synthetic agonists bound. Inside the ligand pocket, we identify key motifs for the recognition of histamine, the distinct binding orientations of histamine and three subpockets that facilitate the design of specific ligands. In addition, we also identify key residues responsible for the selectivity of immethridine. Moreover, we reveal distinct structural features as determinants of Gq vs. Gs or Gs vs. Gi coupling differences among the histamine receptors. Our study provides a structural framework for understanding the ligand recognition and G protein coupling of all 4 histamine receptors, which may facilitate the rational design of ligands targeting these receptors.
Authors
- Guibing Liu (ORCID: https://orcid.org/0009-0005-7555-0167)
- Jingjing Sun (ORCID: https://orcid.org/0000-0002-6892-8177)
- Tianyao Zhang
- Chao Zhang (ORCID: https://orcid.org/0000-0001-8760-0110)
- Xinyuan Shen (ORCID: https://orcid.org/0009-0005-9057-4589)
- Canyang Niu
- Ya-Ni Zhong (ORCID: https://orcid.org/0000-0001-9079-7081)
- Weimin Gong
- Xuan Zhang (ORCID: https://orcid.org/0000-0002-4276-6464)
- Jin‐Peng Sun (ORCID: https://orcid.org/0000-0003-3572-1580)
- Lejin Yang (ORCID: https://orcid.org/0000-0001-9475-6914)
- Ru Zhang (ORCID: https://orcid.org/0000-0002-4860-7800)
- Xiu Li (ORCID: https://orcid.org/0009-0006-6150-6859)
- Peng Xiao (ORCID: https://orcid.org/0000-0002-9809-3481)
- Xuanyu Pu
- Chuan-Cheng Yang
Institutions
- University of Science and Technology of China (CN)
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Shandong University (CN)
- University of Pittsburgh (US)
- Ministry of Education (RO)
- Qilu Hospital of Shandong University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52585-y
- Citations
- 14
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Shandong University
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- University of Science and Technology of China
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
- National Science Fund for Distinguished Young Scholars