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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, M. S. P. (Mark S. P.), Gedeck, Peter, Gosling, Martin, Cox, B. (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, Volume 47 (Number 28). pp. 7414-7422. doi:10.1021/bi800475j ISSN 0006-2960.
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Official URL: http://dx.doi.org/10.1021/bi800475j
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.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||
Library of Congress Subject Headings (LCSH): | Molecular dynamics -- Computer simulation, Potassium channels, Hydrogen-ion concentration | ||||
Journal or Publication Title: | Biochemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0006-2960 | ||||
Official Date: | 15 July 2008 | ||||
Dates: |
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Volume: | Volume 47 | ||||
Number: | Number 28 | ||||
Number of Pages: | 9 | ||||
Page Range: | pp. 7414-7422 | ||||
DOI: | 10.1021/bi800475j | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Funder: | Medical Research Council (Great Britain) (MRC), Novartis (Firm), Wellcome Trust (London, England), British Heart Foundation, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC) |
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