title: Role of the pH in state-dependent blockade of hERG currents.
abstract: Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide's mode of action.
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive, Calgary T2N 1N4, Alberta, Canada.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Libin Cardiovascular Institute and Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Health Research Innovation Centre (HRIC) 3280 Hospital Drive NW Calgary AB T2N 4Z6, Alberta, Canada.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive, Calgary T2N 1N4, Alberta, Canada.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Perissinotti
authors.affiliation: Libin Cardiovascular Institute and Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Health Research Innovation Centre (HRIC) 3280 Hospital Drive NW Calgary AB T2N 4Z6, Alberta, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Lees-Miller
authors.affiliation: Libin Cardiovascular Institute and Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Health Research Innovation Centre (HRIC) 3280 Hospital Drive NW Calgary AB T2N 4Z6, Alberta, Canada.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Biophysics, School of Medicine, Bahcesehir University, 34349 Besiktas Campus, Istanbul, Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: Libin Cardiovascular Institute and Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Health Research Innovation Centre (HRIC) 3280 Hospital Drive NW Calgary AB T2N 4Z6, Alberta, Canada.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, Faculty of Science, University of Calgary, 2500 University Drive, Calgary T2N 1N4, Alberta, Canada.
authors.forename: Sergei Yu
authors.initials: SY
authors.lastname: Noskov
mesh_terms: D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D000072237:ERG1 Potassium Channel / Q000737:chemistry* / Q000235:genetics; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide