Saponaro, Andrea ; Krumbach, Jan H. ; Chaves-Sanjuan, Antonio ; Sharifzadeh, Atiyeh Sadat ; Porro, Alessandro ; Castelli, Roberta ; Hamacher, Kay ; Bolognesi, Martino ; DiFrancesco, Dario ; Clarke, Oliver B. ; Thiel, Gerhard ; Moroni, Anna (2024)
Structural determinants of ivabradine block of the open pore of HCN4.
In: Proceedings of the National Academy of Sciences of the United States of America, 121 (27)
doi: 10.1073/pnas.2402259121
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
HCN1-4 channels are the molecular determinants of the I/I 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.
Typ des Eintrags: | Artikel |
---|---|
Erschienen: | 2024 |
Autor(en): | Saponaro, Andrea ; Krumbach, Jan H. ; Chaves-Sanjuan, Antonio ; Sharifzadeh, Atiyeh Sadat ; Porro, Alessandro ; Castelli, Roberta ; Hamacher, Kay ; Bolognesi, Martino ; DiFrancesco, Dario ; Clarke, Oliver B. ; Thiel, Gerhard ; Moroni, Anna |
Art des Eintrags: | Bibliographie |
Titel: | Structural determinants of ivabradine block of the open pore of HCN4 |
Sprache: | Englisch |
Publikationsjahr: | 2 Juli 2024 |
Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Proceedings of the National Academy of Sciences of the United States of America |
Jahrgang/Volume einer Zeitschrift: | 121 |
(Heft-)Nummer: | 27 |
DOI: | 10.1073/pnas.2402259121 |
Kurzbeschreibung (Abstract): | HCN1-4 channels are the molecular determinants of the I/I 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. |
ID-Nummer: | pmid:38917012 |
Zusätzliche Informationen: | Artikel-ID: e2402259121 |
Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Biologie der Algen und Protozoen 10 Fachbereich Biologie > Computational Biology and Simulation |
Hinterlegungsdatum: | 01 Jul 2024 12:20 |
Letzte Änderung: | 01 Jul 2024 12:30 |
PPN: | 519485572 |
Export: | |
Suche nach Titel in: | TUfind oder in Google |
![]() |
Frage zum Eintrag |
Optionen (nur für Redakteure)
![]() |
Redaktionelle Details anzeigen |