Structural Basis of Potassium Channel Drug Interactions

描述（由申请人提供）： 心脏钾通道被认为是许多药物的作用部位，可导致致命性室性心律失常。特别是hERG通道，已被证明是各种药物的靶点，这些药物可引起药物诱导的长QT综合征和尖端扭转型室性心动过速。最近已经表明，hERG在其内部空腔中在类似于KcsA的季铵（QA）位点的位点处结合这些药物。与hERG的药物结合位点的建议位置一致，许多已知的hERG阻断剂显示电压和状态依赖性，这让人想起QA阻断。QA块的电压和状态依赖性的机制是未知的，但我们最近提出，它可能会出现作为一个药物渗透离子相互作用，这本身是电压和状态依赖性的结果。我们推测，药物与hERG钾通道结合的电压和状态依赖性是阻滞剂和渗透离子之间的能量耦合的结果。拟议的实验利用结构和功能的技术来测试我们的假设。

DESCRIPTION (provided by applicant): Cardiac potassium channels have been described as the site of action of many drugs that cause fatal ventricular arrythmias. The hERG channel, in particular, has been shown to be targeted by a variety of drugs that cause drug-induced long QT syndrome and torsades de pointe. Recently it has been shown that hERG binds such drugs in its internal cavity at a site analogous to the quaternary ammonium (QA) site of KcsA. Consistent with the proposed location of hERG's drug-binding site, many known hERG blockers show voltage- and state-dependence that is reminiscent of QA blockade. The mechanism of voltage- and state-dependence of QA block is unknown, but we have recently suggested that it may arise as a result of a drug-permeant ion interaction that is itself voltage- and state-dependent. We hypothesize that voltage- and state-dependence of drug-binding to the hERG potassium channel arises as a result of energetic coupling between blocker and permeant ions. The proposed experiments utilize both structural and functional techniques to test our hypothesis.