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Publication Abstract from PubMed

HCN1-4 channels are the molecular determinants of the I(f)/I(h) 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 A 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.

Structural determinants of ivabradine block of the open pore of HCN4.,Saponaro A, Krumbach JH, Chaves-Sanjuan A, Sharifzadeh AS, Porro A, Castelli R, Hamacher K, Bolognesi M, DiFrancesco D, Clarke OB, Thiel G, Moroni A Proc Natl Acad Sci U S A. 2024 Jul 2;121(27):e2402259121. doi: , 10.1073/pnas.2402259121. Epub 2024 Jun 25. PMID:38917012^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.