RT Journal Article
SR Electronic
T1 The Pore-Lipid Interface: Role of Amino Acid Determinants of Lipophilic Access by Ivabradine to the hERG1 Pore Domain
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.115642
DO 10.1124/mol.118.115642
A1 Henry J Duff
A1 Sergei Y Noskov
A1 Danielle Muruve
A1 German Perlovic
A1 Marina Ol Khovich
A1 Angelica Sharapova
A1 Brenda Gerull
A1 Jiqing Guo
A1 Meryuvert Kudaibergenova
A1 Laura Perissinotti
YR 2019
UL http://molpharm.aspetjournals.org/content/early/2019/06/10/mol.118.115642.abstract
AB 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.