Structural Basis of Potassium Channel Drug Interactions

描述（由申请人提供）： 心脏钾通道被描述为许多导致致命性室性心律失常的药物的作用部位。尤其是 hERG 通道已被证明是多种药物的靶标，这些药物会导致药物诱发的长 QT 综合征和尖端扭转型室速。最近的研究表明，hERG 在其内腔中与 KcsA 的季铵 (QA) 位点类似的位点结合此类药物。与 hERG 药物结合位点的拟议位置一致，许多已知的 hERG 阻断剂表现出电压和状态依赖性，这让人想起 QA 阻断。 QA 阻断的电压和状态依赖性机制尚不清楚，但我们最近提出，它可能是由于药物渗透离子相互作用而产生的，而药物渗透离子相互作用本身是电压和状态依赖性的。我们假设药物与 hERG 钾通道结合的电压和状态依赖性是由于阻断剂和渗透离子之间的能量耦合而产生的。所提出的实验利用结构和功能技术来检验我们的假设。

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.