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死性室性心律失常的药物的作用部位。特别是，HERG通道被证明是各种药物的靶点，这些药物会导致药物诱导的长QT综合征和尖端扭动。最近有研究表明，HERG在其内腔中与这些药物结合的位置类似于KCSA的季铵(QA)位置。与提出的HERG药物结合部位的位置一致，许多已知的HERG阻滞剂表现出电压和状态依赖，这让人想起QA封锁。QA阻滞剂的电压和状态依赖机制尚不清楚，但我们最近提出，它可能是药物与离子相互作用的结果，而药物与离子的相互作用本身就是电压和状态依赖的。我们假设药物与HERG钾通道结合的电压和状态依赖性是阻滞剂和外在离子之间能量耦合的结果。拟议的实验同时利用结构和功能技术来验证我们的假设。

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.