上海交通大学蒋毅研究小组报道了解码配体识别和组胺H3和H4受体的组成性激活。该项研究成果发表在2025年8月28日出版的《中国药理学报》上。

在这项研究中，该研究团队通过低温电子显微镜发现了H4R与一种选择性拮抗剂（adriforant）结合的无活性结构，以及H3R和H4R与组胺络合物的两种si偶联结构。他们的结构和诱变分析提供了对移植物与H4R的选择性结合和组胺受体对组胺的识别的见解。他们的发现还揭示了H3R和H4R的独特拮抗机制，并确定了细胞外环2上芳香氨基酸在调节H3R和H4R组成活性中的作用。这些发现促进了他们对组胺受体功能调节的认识，为神经和免疫相关疾病的靶向治疗的发展提供了基础。

据介绍，组胺H3受体（H3R）和H4受体（H4R）是组胺受体家族的关键成员，H3R是治疗发作性睡病的潜在靶点，H4R是治疗炎症和过敏性疾病的下一代抗组胺药的候选药物。尽管在了解组胺受体结构方面取得了进展，但H3R和H4R的配体识别和受体拮抗的详细机制尚不清楚。

附：英文原文

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

Author: Jin, San-shan, Zhang, Heng, Yan, Jia-hui, Wu, Can-rong, Cai, Xiao-qing, Wu, Kai, Wang, Ming-Wei, Xu, H. Eric, Yang, De-hua, Jiang, Yi

Issue&Volume: 2025-08-28

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.

DOI: 10.1038/s41401-025-01633-4

Source: https://www.nature.com/articles/s41401-025-01633-4