Elucidation of Allosteric Inhibition Mechanism of 2-Cys Human Peroxiredoxin by Molecular Modeling
- Authors
- Kim, Minsup; Lee, Keun Woo; Cho, Art E.
- Issue Date
- 12월-2012
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF CHEMICAL INFORMATION AND MODELING, v.52, no.12, pp.3278 - 3283
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CHEMICAL INFORMATION AND MODELING
- Volume
- 52
- Number
- 12
- Start Page
- 3278
- End Page
- 3283
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/106729
- DOI
- 10.1021/ci3004495
- ISSN
- 1549-9596
- 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.
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