Structural homology between DNA binding sites of DNA polymerase beta and DNA topoisomerase II.
Unsaturated long-chain fatty acids selectively bind to the DNA binding sites of DNA polymerase beta and DNA topoisomerase II, and inhibit their activities, although the amino acid sequences of these enzymes are markedly different from each other. Computer modeling analysis revealed that the fatty acid interaction interface in both enzymes has a group of four amino acid residues in common, forming a pocket which binds to the fatty acid molecule. The four amino acid residues were Thr596, His735, Leu741 and Lys983 for yeast DNA topoisomerase II, corresponding to Thr79, His51, Leu11 and Lys35 for rat DNA polymerase beta. Using three-dimensional structure model analysis, we determined the spatial positioning of specific amino acid residues binding to the fatty acids in DNA topoisomerase II, and subsequently obtained supplementary information to build the structural model.
Mizushina
Y
Y
Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba, 278-8510, Japan.
Sugawara
F
F
Iida
A
A
Sakaguchi
K
K
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D019787:Linoleic Acid / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D020349:Surface Plasmon Resonance; D059005:Topoisomerase II Inhibitors; D015003:Yeasts / Q000201:enzymology
D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D059005:Topoisomerase II Inhibitors; D004247:DNA; C013147:nervonic acid; D019787:Linoleic Acid; D019951:DNA Polymerase beta; D004250:DNA Topoisomerases, Type II