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

Biochemistry. 2008 Jul 15;47(28):7414-22. doi: 10.1021/bi800475j. Epub 2008 Jun 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation
  • Humans
  • Hydrogen-Ion Concentration*
  • Lipid Bilayers
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphatidylcholines
  • Potassium Channels / chemistry*
  • Potassium Channels / physiology*
  • Protein Conformation

Substances

  • Lipid Bilayers
  • Phosphatidylcholines
  • Potassium Channels
  • 1-palmitoyl-2-oleoylphosphatidylcholine