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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

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

Published Date

  • June 2009

Published In

Volume / Issue

  • 284 / 26

Start / End Page

  • 17625 - 17633

PubMed ID

  • 19395383

Pubmed Central ID

  • 19395383

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.003913

Language

  • eng