Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations.
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.
Department of Cell Physiology and Pharmacology, University of Leicester, UK.
Phillip J
PJ
Stansfeld
Alessandro
A
Grottesi
Zara A
ZA
Sands
Mark S P
MS
Sansom
Peter
P
Gedeck
Martin
M
Gosling
Brian
B
Cox
Peter R
PR
Stanfield
John S
JS
Mitcheson
Michael J
MJ
Sutcliffe
D000595:Amino Acid Sequence; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines; D015221:Potassium Channels / Q000737:chemistry* / Q000502:physiology*; D011487:Protein Conformation
D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D015221:Potassium Channels; C028694:1-palmitoyl-2-oleoylphosphatidylcholine