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TitleStructural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine.
Journal, issue, pagesJ Biol Chem, Vol. 300, Issue 11, Page 107798, Year 2024
Publish dateSep 20, 2024
AuthorsTong Che / Wei Zhang / Xinyu Cheng / Sijia Lv / Minqing Zhang / Yuting Zhang / Tingting Yang / Weiwei Nan / Shuangyan Wan / Bo Zeng / Jian Li / Bing Xiong / Jin Zhang /
PubMed AbstractThe hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 ...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 cryo-electron 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 findings reveal that ivabradine binds to a previously unidentified 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.
External linksJ Biol Chem / PubMed:39307309 / PubMed Central
MethodsEM (single particle)
Resolution3.23 Å
Structure data

38961

8y60

EMDB-38961, PDB-8y60:
Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine
Method: EM (single particle) / Resolution: 3.23 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL


ChemComp, No image

ChemComp-VNZ:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels / Ivabradine / complex

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