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TitleStructural determinants of ivabradine block of the open pore of HCN4.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 27, Page e2402259121, Year 2024
Publish dateJul 2, 2024
AuthorsAndrea Saponaro / Jan H Krumbach / Antonio Chaves-Sanjuan / Atiyeh Sadat Sharifzadeh / Alessandro Porro / Roberta Castelli / Kay Hamacher / Martino Bolognesi / Dario DiFrancesco / Oliver B Clarke / Gerhard Thiel / Anna Moroni /
PubMed AbstractHCN1-4 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), ...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.
External linksProc Natl Acad Sci U S A / PubMed:38917012 / PubMed Central
MethodsEM (single particle)
Resolution3.6 Å
Structure data

16860
EMDB entry, No image

8ofi

EMDB-16860, PDB-8ofi:
Ivabradine bound to HCN4 channel
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals


ChemComp, No image

ChemComp-VNZ:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
KeywordsMEMBRANE PROTEIN / HCN channels / ivabradine / ion transport / drug / hearth / hcn4

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