Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations.
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Stansfeld, Phillip J, Grottesi, Alessandro, Sands, Zara A, Sansom, Mark S P, Gedeck, Peter, Gosling, Martin, Cox, Brian, Stanfield, Peter R, Mitcheson, John S and Sutcliffe, Michael J (2008) Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. Biochemistry, 47 (28). pp. 7414-7422. ISSN 1520-4995
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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| Date Deposited: | 14 Dec 2009 13:53 |
| Last Modified: | 14 Dec 2009 13:53 |
| URI: | https://oak.novartis.com/id/eprint/821 |