RT Journal Article SR Electronic T1 Refining Insights into High-Affinity Drug Binding to the Human Ether-à-go-go-Related Gene Potassium Channel JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1592 OP 1595 DO 10.1124/mol.108.047563 VO 73 IS 6 A1 Jules C. Hancox A1 Andrew F. James YR 2008 UL http://molpharm.aspetjournals.org/content/73/6/1592.abstract AB hERG (human ether-à-go-go-related gene) potassium (K+) channels play a crucial role in electrophysiological activity in the heart, exerting a profound influence on ventricular action potential repolarization and on the duration of the QT interval of the electrocardiogram. hERG channels are strongly implicated in the acquired form of long QT syndrome in that they exhibit a unique susceptibility to pharmacological inhibition by therapeutically and chemically diverse drugs. Investigations over a number of years provide compelling evidence that a comparatively large inner cavity and the presence of particular aromatic amino acid residues (Tyr652 and Phe656) on the inner (S6) helices of the channel are important features that allow hERG to accommodate and bind disparate drugs. However, whereas functional hERG channels are composed of four identical subunits, blocking molecules may not interact equally with aromatic residues from each of the four subunits. In this issue of Molecular Pharmacology, Myokai et al. (p. 1643) report for the first time the use of tandem dimers incorporating mutations to Tyr652 and Phe656 to elucidate asymmetric binding of the high affinity hERG inhibitor cisapride. Not only has this approach provided increased information on spatial arrangements involved in cisapride binding to the channel, but it offers a powerful means of refining the wider understanding of hERG channel structure-function in relation to drug binding. The American Society for Pharmacology and Experimental Therapeutics