title: Structural insights into trapping and dissociation of small molecules in K⁺ channels.
abstract: K(+) channels play a critical role in numerous physiological and pathophysiological processes rendering them an attractive target for therapeutic intervention. However, the hERG K(+) channel poses a special challenge in drug discovery, since block of this channel by a plethora of diverse chemical entities can lead to long QT syndrome and sudden death. Of particular interest is the so-called trapping phenomenon, characterized by capture of a drug behind closed channel gates, which harbors an increased pro-arrhythmic risk. In this study we investigated the influence of trapped blockers on the gating dynamics and probed the state dependence of dissociation in K(+) channels by making use of the quaternary tetrabutylammonium. By applying essential dynamics simulations and two-electrode voltage clamp we obtained detailed insights into the dynamics of trapping in KcsA and hERG. Our simulations suggest that the trapped TBA influences the F656 flexibility during gate closure. Based on these findings, we provide a structural hypothesis for drug trapping. Further our simulations reveal the extent of gate opening necessary for drug dissociation.
authors.affiliation: Department for Pharmacology and Toxicology, University of Vienna , Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Linder
authors.forename: Priyanka
authors.initials: P
authors.lastname: Saxena
authors.forename: Eugen
authors.initials: E
authors.lastname: Timin
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Anna
authors.initials: A
authors.lastname: Stary-Weinzinger
mesh_terms: D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D026902:Potassium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000378:metabolism* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; C009405:tetrabutylammonium