Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations

Phillip J. Stansfeld, Alessandro Grottesi, Zara A. Sands, Mark S P Sansom, Peter Gedeck, Martin Gosling, Brian Cox, Peter R. Stanfield, John S. Mitcheson, Michael J. Sutcliffe

    Research output: Contribution to journalArticlepeer-review

    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. © 2008 American Chemical Society.
    Original languageEnglish
    Pages (from-to)7414-7422
    Number of pages8
    JournalBiochemistry
    Volume47
    Issue number28
    DOIs
    Publication statusPublished - 15 Jul 2008

    Keywords

    • RECTIFIER K+ CHANNEL
    • LONG-QT SYNDROME
    • SELECTIVITY FILTER
    • CRYSTAL-STRUCTURE
    • 2-PORE DOMAIN
    • CARDIAC-ARRHYTHMIA
    • INWARD RECTIFIER
    • OUTER MOUTH
    • HERG
    • BLOCK

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