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

Access to files

Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:

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.

Keyword(s)

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

Bibliographic metadata

Institutional metadata

Record metadata