Three-Dimensional Structural Model Analysis of the Binding Site of Lithocholic Acid, an Inhibitor of DNA Polymerase β and DNA Topoisomerase II

Yoshiyuki Mizushina; Nobuyuki Kasai; Fumio Sugawara; Akira Iida; Hiromi Yoshida; Kengo Sakaguchi

Yoshiyuki Mizushina, Nobuyuki Kasai, Fumio Sugawara, Akira Iida, Hiromi Yoshida, Kengo Sakaguchi

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Keywords: DNA polymerase β, DNA topoisomerase II, docking simulation, enzyme inhibitor, interaction interface, lithocholic acid

JOURNAL FREE ACCESS

2001 Volume 130 Issue 5 Pages 657-664

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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 II). No other DNA metabolic enzymes tested were affected by LCA. Therefore, LCA should be classified as an inhibitor of both pol β and topo II. 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 II. 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 II are three-dimensionally very similar.

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