title: Elucidation of allosteric inhibition mechanism of 2-Cys human peroxiredoxin by molecular modeling.
abstract: We used molecular dynamics (MD) simulations and protein docking to elucidate the mechanism of allosteric inhibition of the human form of peroxiredoxin (Prx), 2-Cys proliferation associated gene (PAG). Beginning by using the rat form of Prx, 2-Cys heme-binding protein as a template, we used homology modeling to find the structure of human 2-Cys PAG, which is in dimeric form. Molecular dynamics simulations showed that the structure of the reduced form of the 2-Cys PAG dimer fluctuates as the two monomers drift away and approach each other. We then used SiteMap to search for binding sites on the surface of this dimer. A binding site between the two monomers was found, and virtual screening with docking was performed to identify a ligand binding to this site. Subsequent MD simulation revealed that with this ligand in the binding site, the dimer structure of 2-Cys PAG becomes stabilized such that two cysteine residues from two monomers, which are partners of a disulfide bond of the oxidized form, remain separated. This mechanism can be used as an allosteric inhibition of Prx as a hydrogen peroxide reducer, the role of which has been studied as an anticancer drug target.
authors.affiliation: Department of Bioinformatics, Korea University, Sejong, Korea.
authors.forename: Minsup
authors.initials: M
authors.lastname: Kim
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Art E
authors.initials: AE
authors.lastname: Cho
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D054464:Peroxiredoxins