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Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine

文献类型：期刊论文

作者Che, Tong7,8; Zhang, Wei7,8; Cheng, Xinyu7,8; Lv, Sijia7,8; Zhang, Minqing7,8; Zhang, Yuting6; Yang, Tingting7,8; Nan, Weiwei6; Wan, Shuangyan7,8; Zeng, Bo3,4,5
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2024-11-01
卷号300期号:11页码:9
DOI10.1016/j.jbc.2024.107798
通讯作者Li, Jian(rmsl_2040@163.com) ; Xiong, Bing(bxiong@simm.ac.cn) ; Zhang, Jin(zhangxiaokong@hotmail.com)
英文摘要The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryoelectron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our fi ndings reveal that ivabradine binds to a previously unidentified fi ed pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration- approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area.
WOS关键词MOVEMENTS ; TARGETS ; BLOCK
资助项目National Natural Science Foundation of China[32271260] ; Jiangxi Province Natural Science Foundation[20224ACB206046] ; Jiangxi Natural Science Foundation for Distinguished Young Scholars[20212ACB216001] ; Jiangxi Key Research and Development Program[20203BBG73063] ; Jiangxi Double Thousand Plan[jxsq2019101064] ; Foundation of Gannan Medical University[QD201910]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:001337137600001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/313975]  
专题中国科学院上海药物研究所
通讯作者Li, Jian; Xiong, Bing; Zhang, Jin
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China
2.Gannan Med Univ, Coll Pharm, Ganzhou, Jiangxi, Peoples R China
3.Southwest Med Univ, Dept Endocrinol, Affiliated Hosp, Luzhou, Sichuan, Peoples R China
4.Southwest Med Univ, Inst Cardiovasc Res, Luzhou, Sichuan, Peoples R China
5.Southwest Med Univ, Key Lab Med Electrophysiol, Minist Educ & Sichuan Prov, Luzhou, Sichuan, Peoples R China
6.Shenzhen Crystalo Biopharmaceut Co Ltd, Shenzhen 518118, Guangdong, Peoples R China
7.Nanchang Univ, Affiliated Hosp 2, Jiangxi Med Coll, Nanchang, Jiangxi, Peoples R China
8.Nanchang Univ, Jiangxi Med Coll, MOE Basic Res & Innovat Ctr Targeted Therapeut Sol, Sch Basic Med Sci, Nanchang, Jiangxi, Peoples R China
推荐引用方式
GB/T 7714		 Che, Tong,Zhang, Wei,Cheng, Xinyu,et al. Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2024,300(11):9.
APA Che, Tong.,Zhang, Wei.,Cheng, Xinyu.,Lv, Sijia.,Zhang, Minqing.,...&Zhang, Jin.(2024).Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine.JOURNAL OF BIOLOGICAL CHEMISTRY,300(11),9.
MLA Che, Tong,et al."Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine".JOURNAL OF BIOLOGICAL CHEMISTRY 300.11(2024):9.

入库方式： OAI收割

来源：上海药物研究所

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