title: Side pockets provide the basis for a new mechanism of Kv channel-specific inhibition.
abstract: Most known small-molecule inhibitors of voltage-gated ion channels have poor subtype specificity because they interact with a highly conserved binding site in the central cavity. Using alanine-scanning mutagenesis, electrophysiological recordings and molecular modeling, we have identified a new drug-binding site in Kv1.x channels. We report that Psora-4 can discriminate between related Kv channel subtypes because, in addition to binding the central pore cavity, it binds a second, less conserved site located in side pockets formed by the backsides of S5 and S6, the S4-S5 linker, part of the voltage sensor and the pore helix. Simultaneous drug occupation of both binding sites results in an extremely stable nonconducting state that confers high affinity, cooperativity, use-dependence and selectivity to Psora-4 inhibition of Kv1.x channels. This new mechanism of inhibition represents a molecular basis for the development of a new class of allosteric and selective voltage-gated channel inhibitors.
authors.affiliation: Institute for Physiology and Pathophysiology, University of Marburg, Marburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Marzian
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stansfeld
authors.forename: Markus
authors.initials: M
authors.lastname: Rapedius
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nematian-Ardestani
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Klaus
authors.initials: K
authors.lastname: Steinmeyer
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
mesh_terms: D005363:Ficusin / Q000737:chemistry / Q000494:pharmacology; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C499898:5-(4-phenylbutoxy)psoralen; D051666:Kv1.5 Potassium Channel; D005363:Ficusin