Combination of Autodisplay and Dynamic Pharmacophore Modeling Reveals New Insights into Cyclic Nucleotide Binding in Hyperpolarization-Activated and Cyclic Nucleotide-Gated Ion Channel 4 (HCN4).

ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels play a critical role in regulating neuronal and cardiac rhythmicity, with their function being modulated by cyclic nucleotide binding. Dysfunction of HCN ion channels leads to the genesis of several diseases such as arrhythmia, bradycardia, or epilepsy. This study employs a multidisciplinary approach integrating mutagenesis, ligand binding assays, and molecular dynamics (MD) simulations combined with dynamic pharmacophore studies to investigate the impact of single residue mutations within the cyclic nucleotide-binding domain (CNBD) of HCN4 channels. Utilizing an autodisplay-based ligand binding assay, surface-displayed HCN4 CNBD mutants were evaluated for their interaction with 8-Fluo-cAMP, providing insights into the

SUBMITTER: Wojciechowski MN 

PROVIDER: S-EPMC11651207 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature