Psalmotoxin-1 docking to human acid-sensing ion channel-1

Academic Article

Abstract

  • Acid-sensing ion channel-1 (ASIC-1) is a proton-gated ion channel implicated in nociception and neuronal death during ischemia. Recently the first crystal structure of a chicken ASIC was obtained. Expanding upon this work, homology models of the human ASICs were constructed and evaluated. Energy-minimized structures were tested for validity by in silico docking of the models to psalmotoxin-1, which potently inhibits ASIC-1 and not other members of the family. The data are consistent with prior radioligand binding and functional assays while also explaining the selectivity of PcTX-1 for homomeric hASIC-1a. Binding energy calculations suggest that the toxin and channel create a complex that is more stable than the channel alone. The binding is dominated by the coulombic contributions, which account for why the toxin-channel interaction is not observed at low pH. The computational data were experimentally verified with single channel and whole-cell electrophysiological studies. These validated models should allow for the rational design of specific and potent peptidomimetic compounds that may be useful for the treatment of pain or ischemic stroke. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Qadri YJ; Berdiev BK; Song Y; Lippton HL; Fuller CM; Benos DJ
  • Start Page

  • 17625
  • End Page

  • 17633
  • Volume

  • 284
  • Issue

  • 26