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

文献类型：期刊论文

作者Jin, San-shan2,9; Zhang, Heng3; Yan, Jia-hui4,5; Wu, Can-rong3,6; Cai, Xiao-qing4,7; Wu, Kai3,8; Wang, Ming-Wei1,6; Xu, H. Eric3,5,6,8; Yang, De-hua4,5,7; Jiang, Yi2,9,10
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-08-28
页码11
关键词histamine receptor H3 histamine receptor H4 adriforant histamine constitutive activity
ISSN号1671-4083
DOI10.1038/s41401-025-01633-4
英文摘要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.
WOS关键词CRYO-EM STRUCTURE ; H-3 RECEPTOR ; ALLERGIC INFLAMMATION ; SOFTWARE ; RELEASE ; COMPLEX ; MODEL
资助项目National Key R&D Program of China[2022YFC2703105] ; National Key R&D Program of China[LG-GG-202204-01] ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82273985] ; National Natural Science Foundation of China[82273961] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; National Key Basic Research Program of China[2023YFA1800804] ; Shanghai Municipality Science and Technology Development Fund[21JC1401600] ; Program of Shanghai Academic/Technology Research Leader[23XD1400900] ; Sanya Science and Technology Innovation Special Project[2022KJCX77]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001559374700001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/321342]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Xu, H. Eric; Yang, De-hua; Jiang, Yi
作者单位1.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Shanghai Adv Electron Microscope Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
10.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Jin, San-shan,Zhang, Heng,Yan, Jia-hui,et al. Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors[J]. ACTA PHARMACOLOGICA SINICA,2025:11.
APA Jin, San-shan.,Zhang, Heng.,Yan, Jia-hui.,Wu, Can-rong.,Cai, Xiao-qing.,...&Jiang, Yi.(2025).Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors.ACTA PHARMACOLOGICA SINICA,11.
MLA Jin, San-shan,et al."Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors".ACTA PHARMACOLOGICA SINICA (2025):11.

入库方式： OAI收割

来源：上海药物研究所

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