2. Academic Validation
  3. Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors

Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors

  • Acta Pharmacol Sin. 2025 Aug 28. doi: 10.1038/s41401-025-01633-4.
San-Shan Jin # 1 2,  Heng Zhang # 3,  Jia-Hui Yan # 4 5,  Can-Rong Wu 3 6,  Xiao-Qing Cai 4 7,  Kai Wu 3 8,  Ming-Wei Wang 6 9,  H Eric Xu 10 11 12 13,  De-Hua Yang 14 15 16,  Yi Jiang 17 18 19
Affiliations

Affiliations

  • 1 Lingang Laboratory, Shanghai, 200031, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 8 The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 9 Research Center for Deepsea Bioresources, Sanya, 572025, China.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. eric.xu@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, 100049, China. eric.xu@simm.ac.cn.
  • 12 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. eric.xu@simm.ac.cn.
  • 13 The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. eric.xu@simm.ac.cn.
  • 14 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. dhyang@simm.ac.cn.
  • 15 University of Chinese Academy of Sciences, Beijing, 100049, China. dhyang@simm.ac.cn.
  • 16 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. dhyang@simm.ac.cn.
  • 17 Lingang Laboratory, Shanghai, 200031, China. yjiang@lglab.ac.cn.
  • 18 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. yjiang@lglab.ac.cn.
  • 19 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. yjiang@lglab.ac.cn.
  • # Contributed equally.
PMID: 40877594 DOI: 10.1038/s41401-025-01633-4
Abstract

Histamine H3 receptor (H3R) and H4 receptor (H4R) are key members of the Histamine Receptor family, with H3R as a potential target for narcolepsy treatments and H4R as a candidate for next-generation antihistamines for inflammatory and allergic diseases. Although progress has been made in understanding the structure of histamine receptors, the detailed mechanisms of ligand recognition and receptor antagonism for H3R and H4R remain unclear. In this study, using cryo-electron microscopy, we present an inactive structure of H4R bound to a selective antagonist, adriforant, and two Gi-coupled structures of H3R and H4R in complex with histamine. Our structural and mutagenesis analyses provide insights into the selective binding of adriforant to H4R and the recognition of histamine across histamine receptors. Our findings also uncovered distinct antagonistic mechanisms for H3R and H4R and identified the role of aromatic Amino acids on extracellular loop 2 in modulating the constitutive activity of H3R and H4R. These findings advance our knowledge of the functional modulation of histamine receptors, providing a foundation for the development of targeted therapeutics for neurological and immune-related disorders.

Keywords

adriforant; constitutive activity; histamine; histamine receptor H3; histamine receptor H4.

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