? The purpose of the proposed set of experiments is to examine the intracellular N-terminal domain of the HERG voltage-gated potassium channel. A portion of the N-terminal region is structurally homologous to PAS Domains - ubiquitous structural motifs involved in sensory transduction that are found in a variety of sensory proteins. A number of PAS domains have been found to be associated with bound cofactors through which these PAS domain-containing proteins detect changes in environmental variables and effect signaling change. Two main approaches will be used to discover molecules that affect the HERG PAS domain, an experimental approach that borrows from the disciplines of molecular biology, biochemistry, and NMR, as well as a theoretical approach involving computational protein study and virtual library screening. Lead compounds that are hypothesized to affect the PAS domain derived from any aspects of this project will be experimentally examined for their ability to alter the biophysics of functional HERG channels heterologously expressed in Xenopus oocytes. ? ?