title: New potential binding determinant for hERG channel inhibitors.
abstract: Human ether-à-go-go related gene (hERG) 1 channels conduct the rapid delayed rectifier K(+) current (IKr) and are essential for the repolarization of the cardiac action potential. hERG1 inhibition by structurally diverse drugs may lead to life threatening arrhythmia. Putative binding determinants of hERG1 channel blockers include T623, S624 and V625 on the pore helix, and residues G648, Y652 and F656, located on segment S6. We and others have previously hypothesized that additional binding determinants may be located on helix S5, which is in close contact with the S6 segments. In order to test this hypothesis, we performed a detailed investigation combining ionic current measurements with two-microelectrode voltage clamp and molecular modeling techniques. We identified a novel aromatic high affinity binding determinant for blockers located in helix S5, F557, which is equally potent as Y652. Modeling supports a direct interaction with the outer pore helix.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Saxena
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: E-M
authors.initials: EM
authors.lastname: Zangerl-Plessl
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Linder
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Windisch
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Hohaus
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Timin
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Hering
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Stary-Weinzinger
mesh_terms: D001665:Binding Sites; D000072237:ERG1 Potassium Channel / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000072237:ERG1 Potassium Channel; D026902:Potassium Channel Blockers