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Recent X-ray crystal structures of the two-pore domain (K2P) family of potassium channels have revealed a unique structural architecture at the point where the cytoplasmic bundle-crossing gate is found in most other tetrameric K(+) channels. However, despite the apparently open nature of the inner pore in the TWIK-1 (K2P1/KCNK1) crystal structure, the reasons underlying its low levels of functional activity remain unclear. In this study, we use a combination of molecular dynamics simulations and functional validation to demonstrate that TWIK-1 possesses a hydrophobic barrier deep within the inner pore, and that stochastic dewetting of this hydrophobic constriction acts as a major barrier to ion conduction. These results not only provide an important insight into the mechanisms which control TWIK-1 channel activity, but also have important implications for our understanding of how ion permeation may be controlled in similar ion channels and pores.

Original publication

DOI

10.1038/ncomms5377

Type

Journal article

Journal

Nat Commun

Publication Date

08/07/2014

Volume

5

Keywords

Animals, Humans, Hydrophobic and Hydrophilic Interactions, Lipid Bilayers, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Potassium Channels, Tandem Pore Domain, Protein Conformation, Water, Xenopus