Molecular basis for state-dependent drug block of Kv11.1 (human ether-à-go-go-related gene) potassium channels

Many structurally and therapeutically diverse drugs block the human ether-à-go-go-related gene (HERG) potassium channel, predisposing patients to an increased risk of arrhythmias and sudden cardiac death. Many of these drugs show state dependence of block, exhibiting a greater preference for block of the inactivated state. Four key residues, ie, T623, S624, Y652, and F656, within the central pore cavity of HERG have been implicated in drug binding. However, whether drugs bind differently to these key residues to dictate preference for binding to the inactivated over the open state is not known. We used the SyncroPatch 384PE, automated patch clamp platform to measure how drug block was impacted by point mutations at these 4 residues when introduced into wild-type (WT) HERG (preferentially occupies the inactivated state) and N588K-HERG (preferentially occupies the open state) channels at depolarized potentials. Mutations to Y652 and F656, which abolished aromatic and hydrophobic characteristics, respectively, reduced drug binding in both WT and N588K backgrounds. The S624A mutation attenuated block by cisapride, astemizole, and quinidine in the WT background but not in the N588K background. We suggest that relative movements between the polar S624 sidechain and the aromatic Y652 sidechains in WT (inactivated) compared with N588K (open) channels can explain preferential binding to the inactivated state. An improved understanding of the structural basis of where and how drugs bind to HERG channels should facilitate efforts to reduce inadvertent HERG drug block during the drug development process. SIGNIFICANCE STATEMENT: A diverse range of drugs block human ether-à-go-go-related gene (HERG) potassium channels, which can have serious side effects, including sudden death. Most problematic drugs bind to the inactivated state of HERG channels. This study shows that the polar side chain of Ser624, at the base of the selectivity filter, is critical for preferential drug block of inactivated compared with open channels. A better understanding of state-dependent drug binding should facilitate efforts to reduce inadvertent HERG drug block.