8OFI

Ivabradine bound to HCN4 channel

Summary for 8OFI

• Entry DOI: 10.2210/pdb8ofi/pdb
• EMDB information: 16860
• Descriptor: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, Ivabradine (2 entities in total)
• Functional Keywords: hcn channels, ivabradine, ion transport, membrane protein, drug, hearth, hcn4
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 4
• Total formula weight: 394559.49

Authors

Saponaro, A.,Chaves-Sanjuan, A.,Sharifzadeh, A.S.,Clarke, O.B.,Marabelli, C.,Bolognesi, M.,Thiel, G.,Moroni, A. (deposition date: 2023-03-15, release date: 2024-08-14)

Primary citation

Saponaro, A.,Krumbach, J.H.,Chaves-Sanjuan, A.,Sharifzadeh, A.S.,Porro, A.,Castelli, R.,Hamacher, K.,Bolognesi, M.,DiFrancesco, D.,Clarke, O.B.,Thiel, G.,Moroni, A.
Structural determinants of ivabradine block of the open pore of HCN4.
Proc.Natl.Acad.Sci.USA, 121:e2402259121-e2402259121, 2024

PubMed 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.

PubMed: 38917012
DOI: 10.1073/pnas.2402259121

Experimental method

ELECTRON MICROSCOPY (3.6 Å)