Abstract
Abnormal cardiac electrical activity is a common side effect caused by unintended block of the promiscuous drug target hERG1; the pore-forming domain of the delayed rectifier K+ channel in the heart. hERG1 block leads to prolongation of the QT interval on the ECG, a phase of the cardiac cycle that underlies myocyte repolarization. Even newly released anti-arrhythmic drugs, such as ivabradine, block the IKr, prolong action potential duration (APD) and induce potentially lethal arrhythmia known as Torsades de Pointes (TdP). In this study, we describe a critical drug-binding pocket adjacent to a lipid-facing surface of hERG1 channel. Our data show that the block exhibited by ivabradine is strongly associated with a conserved binding pocket on the lateral pore-surface facing the lipid. Mutations at this conserved M651 residue alter block induced by ivabradine but not of dofetilide. As revealed by MD simulations, binding of ivabradine to a lipophilic pore access site is coupled to a state-dependent reorientation of aromatic residues F557 and F656 in the S5 and S6 helices. We show the M651 mutation impedes state-dependent dynamics of F557 and F656 aromatic cassette at the protein-lipid interface which has a potential to disrupt drug induced block of the channel. This fundamentally new mechanism coupling the channel dynamics and small-molecule access from the membrane into the hERG1 intra-cavitary site provides a simple rational for the well-established state-dependence of drug blockade.
SIGNIFICANCE STATEMENT The drug interferance with the function of with cardiac hERG channels represents one of the major sources of drug-induced heart disturbances. We found novel and critical drug-binding pocket adjacent to a lipid-facing surface of hERG1 channel.
- The American Society for Pharmacology and Experimental Therapeutics