Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations |
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Authors: | Stansfeld Phillip J Grottesi Alessandro Sands Zara A Sansom Mark S P Gedeck Peter Gosling Martin Cox Brian Stanfield Peter R Mitcheson John S Sutcliffe Michael J |
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Affiliation: | Department of Cell Physiology and Pharmacology, University of Leicester, UK. |
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Abstract: | Potassium (K (+)) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K (+) channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S 0 K (+) binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K (+) ions through the selectivity filter. |
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