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

Authors
  • Qadri, Yawar J
  • Berdiev, Bakhrom K
  • Song, Yuhua
  • Lippton, Howard L
  • Fuller, Catherine M
  • Benos, Dale J
Type
Published Article
Journal
The Journal of biological chemistry
Publication Date
Jun 26, 2009
Volume
284
Issue
26
Pages
17625–17633
Identifiers
DOI: 10.1074/jbc.M109.003913
PMID: 19395383
Source
Medline
License
Unknown

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.

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