Molecular determinants of hERG potassium channel inhibition by disopyramide

► hERG K+ channels regulate cardiac action potential repolarization. ► Molecular determinants of hERG block by the Class Ia antiarrhythmic disopyramide were studied. ► S6 helical residues Y652 and F656 contribute to disopyramide binding. ► Interactions with pore helical residues are not necessary for disopyramide binding.