Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors
San-shan Jin1,2,
Heng Zhang3,
Jia-hui Yan4,5,
Can-rong Wu3,6,
Xiao-qing Cai4,7,
Kai Wu3,8,
Ming-Wei Wang6,9,
H. Eric Xu3,5,6,8,
De-hua Yang4,5,7,
Yi Jiang1,2,10
1 ingang Laboratory, Shanghai 200031, China
2 chool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
3 tate Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 ational Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5 niversity of Chinese Academy of Sciences, Beijing 100049, China
6 esearch 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 tate Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
8 he Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
9 esearch Center for Deepsea Bioresources, Sanya 572025, China
10 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
Correspondence to: H. Eric Xu: eric.xu@simm.ac.cn, De-hua Yang: dhyang@simm.ac.cn, Yi Jiang: yjiang@lglab.ac.cn,
DOI: 10.1038/s41401-025-01633-4
Received: 8 February 2025
Accepted: 6 July 2025
Advance online: 28 August 2025
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:
histamine receptor H3; histamine receptor H4; adriforant; histamine; constitutive activity
