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|Title:||Molecular modelling of potassium channels|
|Authors:||Stansfield, Phillip James|
|Presented at:||University of Leicester|
|Abstract:||This study uses the structural coordinates of the determined K+ channels to create comparative models of three diverse members of this family, with the aim of enabling a better understanding of the function of these channels. The K+ channel of primary interest is the hERG K+ channel. The pharmacology of this channel is of considerable interest as serendipitous block of K+ conduction pore may result in cardiac arrest. A set of known antagonists have been docked into novel comparative models of hERG to propose how these drugs interact with the channel. The models have also been subjected to molecular dynamics simulations to investigate the drug binding in more detail and to gain a structural understanding of two critical biophysical properties of this channel: activation and inactivation. Additionally, ancillary domains of the channel have been modelled to provide a tool for interpreting detailed structure-function relationships for the hERG channel. The second channel investigated is the TASK-1 channel. Comparative models of this channel have been created to evaluate mutations that alter selectivity and pH sensitivity. The final K+ channel studied is the Kir2.1 channel. A fundamental property of this channel is its block by polyamines, which prevents the efflux of K+. Comparative models have been created, with a series of polyamine analogues docked into the membrane and cytoplasmic pore regions of this channel. Overall, this study has illuminated the structural basis of several biophysical properties that are intrinsic to normal K+ channel function..|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Cell Physiology and Pharmacology|
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