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- Title
Three-Dimensional Structural Model Analysis of the Binding Site of Lithocholic Acid, an Inhibitor of DNA Polymerase β and DNA Topoisomerase II1.
- Authors
Mizushina, Yoshiyuki; Kasai, Nobuyuki; Sugawara, Fumio; Iida, Akira; Yoshida, Hiromi; Sakaguchi, Kengo
- Abstract
The molecular action of lithocholic acid (LCA), a selective inhibitor of mammalian DNA polymerase β (pol β), was investigated. We found that LCA could also strongly inhibit the activity of human DNA topoisomerase II (topo DI). No other DNA metabolic enzymes tested were affected by LCA. Therefore, LCA should be classified as an inhibitor of both pol β and topo EL Here, we report the molecular interaction of LCA with pol β and topo II. By three-dimensional structural model analysis and by comparison with the spatial positioning of specific amino acids binding to LCA on pol β (Lys60, Leu77, and Thr79), we obtained supplementary information that allowed us to build a structural model of topo DI. Modeling analysis revealed that the LCA-interaction interface in both enzymes has a pocket comprised of three amino acids in common, which binds to the LCA molecule. In topo II, the three amino acid residues were Lys720, Leu760, and Thr791. These results suggested that the LCA binding domains of pol β and topo DI are three-dimen-sionally very similar.
- Subjects
LITHOCHOLIC acid; DNA polymerases; DNA topoisomerases; ENZYMES; AMINO acids
- Publication
Journal of Biochemistry, 2001, Vol 130, Issue 5, p657
- ISSN
0021-924X
- Publication type
Article
- DOI
10.1093/oxfordjournals.jbchem.a003031