8y60

Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine

spinqualitylabelsall models 8y60, resolution 3.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8y60 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.23Å Ligands: CLR, VNZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease HCN1_HUMAN Early infantile epileptic encephalopathy. The disease is caused by mutations affecting the gene represented in this entry. Function HCN1_HUMAN Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli. Publication Abstract from PubMed The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our findings reveal that ivabradine binds to a previously unidentified pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration-approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area. Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine.,Che T, Zhang W, Cheng X, Lv S, Zhang M, Zhang Y, Yang T, Nan W, Wan S, Zeng B, Li J, Xiong B, Zhang J J Biol Chem. 2024 Nov;300(11):107798. doi: 10.1016/j.jbc.2024.107798. Epub 2024 , Sep 20. PMID:39307309 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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