Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: 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

Journal, date & volume: Biochemistry, 2008 Jul 15 , 47, 7414-22

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18558719

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.