ArticlePloS one2011
In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate.Frontiers in molecular biosciences · 2023Article
- Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression.Scientific reports · 2020Article
- Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KiScience · 2020Article
- Article
- Probing the molecular basis of hERG drug block with unnatural amino acids.Scientific reports · 2018Article
- Drug trapping in hERG KMedChemComm · 2016Article
- Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects.Acta pharmacologica Sinica · 2014Review
- Exploring the structure of the voltage-gated Na+ channel by an engineered drug access pathway to the receptor site for local anesthetics.The Journal of biological chemistry · 2014Article
- Assessing hERG pore models as templates for drug docking using published experimental constraints: the inactivated state in the context of drug block.Journal of chemical information and modeling · 2014Article
- Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.British journal of pharmacology · 2013Article
- ICA-105574 interacts with a common binding site to elicit opposite effects on inactivation gating of EAG and ERG potassium channels.Molecular pharmacology · 2013Article
- Probing the energy landscape of activation gating of the bacterial potassium channel KcsA.PLoS computational biology · 2013Article
- Modeling and simulation of ion channels.Chemical reviews · 2012Review
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Authors and funding
5 authors.
Funding
Abstract
Pharmacological inhibition of cardiac hERG K(+) channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652) substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.
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