Molecular Basis for state-dependent drug block of Kv11.1 (HERG)
potassium channels
Abstract
Background and Purpose: 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 arrythmias and
sudden cardiac death. Many drugs show state-dependence of block,
exhibiting a greater preference for block of the inactivated state. Five
key residues 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 the inactivated over the open state
is not known. Experimental Approach: We used the SyncroPatch 384PE,
automated patch clamp platform to measure how drug block was impacted by
point mutations at residues T623, S624, Y652, and F656 when introduced
into wild-type HERG (preferentially occupies the inactivated state) and
N588K-HERG (preferentially occupies the open state) channels at
depolarised potentials. Key Results: Mutations to Y652 and F656, that
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. Conclusion and Implications:
We suggest that relative movements between the polar S624 sidechain and
the aromatic Y652 and F656 sidechains in WT (inactivated) compared to
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.