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Structural determinants of ivabradine block of the open pore of HCN4.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 02; Vol. 121 (27), pp. e2402259121. Date of Electronic Publication: 2024 Jun 25. - Publication Year :
- 2024
-
Abstract
- HCN1-4 channels are the molecular determinants of the I <subscript>f</subscript> /I <subscript>h</subscript> 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.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.
- Subjects :
- Humans
Cryoelectron Microscopy
Animals
Potassium Channels chemistry
Potassium Channels metabolism
Muscle Proteins chemistry
Muscle Proteins metabolism
Ivabradine chemistry
Ivabradine pharmacology
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels chemistry
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels metabolism
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels antagonists & inhibitors
Molecular Dynamics Simulation
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 38917012
- Full Text :
- https://doi.org/10.1073/pnas.2402259121