Structural determinants of ivabradine block of the open pore of HCN4.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38917012.
- Also identified by DOI 10.1073/pnas.2402259121 and PMC identifier 11228525.
- Licence recorded as CC BY-NC-ND.
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Abstract
HCN1-4 channels are the molecular determinants of the I<sub>f</sub>/I<sub>h</sub> current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
Medical subject headings
- Ivabradine
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
- Molecular Dynamics Simulation