Probing the Potassium Channel Inhibitor Binding Site

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DESCRIPTION (provided by applicant): Potassium channels contain a conserved ion conduction pore that contains a promiscuous ligand binding site able to bind a multitude of drugs. Determining the precise location of the site, and the mechanism by which binding occurs has been elusive. Small sequence differences in the channels affect hydrophobicity, aromaticity, cavity size, and channel gating which are all thought to affect ligand binding affinity. KcsA, the bacterial channel of known structure, is a suitable model for studying the pore region of the family of potassium channels due to the relative ease with which it can be mutated, highly expressed, and crystallized, I propose to establish a system using the KcsA potassium channel to study the features of the channel cavity using mutagenesis along with both structural biology and electrophysiology methods. I will also express and crystallize HERG (human ether-a-go-go-related gene), a potassium channel present in heart muscle cells. HERG is of particular interest because many common drugs block its channel causing loss of function, which results in an abnormal electrical signal (long-QT syndrome) that can lead to the arrythmia Torsades de Pointes and sometimes sudden heart failure.