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Molecular Modeling of Acid Sensing Ion Channels
Author(s) -
Qadri Yawar J,
Fuller Catherine M,
Benos Dale J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.937.28
Subject(s) - acid sensing ion channel , epithelial sodium channel , amiloride , ion channel , sodium channel , docking (animal) , in silico , homology modeling , modeller , chemistry , computational biology , biophysics , biology , microbiology and biotechnology , biochemistry , sodium , medicine , receptor , gene , nursing , organic chemistry , enzyme
Acid sensing ion channels (ASIC) proteins are a subfamily of the Degenerin/Epithelial Sodium Channel (ENaC) superfamily of proteins. These proteins interact with themselves and other family members to form diverse ion channels implicated in numerous physiological and pathophysiological processes such as hypertension and nociception and are all inhibited by amiloride. Recently, the first crystal structure of a galline member of this family was obtained, allowing a look at the exact structure and arrangement of the channel complex. However, functional and pharmacological data of chicken ion channels are limited. Using MODELLER 9v2, homology models of the better characterized huASIC‐1b, huASIC‐2b, and αβγ‐huENaC channels were derived. While both ASIC‐1 and ASIC‐2 models appear similar to the template structure, models of ENaC channels diverge with several undefined domains, suggesting that ENaCs may be structurally different from ASICs. Regardless, with models in hand, it is now possible to perform in silico screening to find novel small molecule inhibitors. Preliminary inhibitor docking studies for amiloride are consistent with sites described in the literature as critical for amiloride inhibition. Further work will use molecular dynamics to better optimize the models and to further examine inhibitor interactions with ASIC/ENaC channels. This study was supported by NIH Grant CA101952 and DK37206.