Interaction model for anthracycline activity against DNA topoisomerase II.
DNA topoisomerase II (Top2) is an essential nuclear enzyme and a target of very effective anticancer drugs including anthracycline antibiotics. Even though several aspects of drug activity against Top2 are understood, the drug receptor site is not yet known. Several Top2 mutants have altered drug sensitivity and have provided information of structural features determining drug action. Here, we have investigated the sensitivity to three closely related anthracycline derivatives of yeast Top2 bearing mutations in the CAP-like domain and integrated the findings with computer models of ternary drug-enzyme-DNA complexes. The results suggest a model for the anthracycline receptor wherein a drug molecule has specific interactions with the cleaved DNA as well as amino acid residues of the CAP-like domain of an enzyme monomer. The drug molecule is intercalated into DNA at the site of cleavage, and interestingly, drug-enzyme contacts involve one side of the four-ring chromophore and the side chain of the anthracycline molecule. The findings may explain several established structure-activity relationships of antitumor anthracyclines and may thus provide a framework for further developments of effective Top2 poisons.
Moro
Stefano
S
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, Padova, Italy.
Beretta
Giovanni L
GL
Dal Ben
Diego
D
Nitiss
John
J
Palumbo
Manlio
M
Capranico
Giovanni
G
D018943:Anthracyclines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D017434:Protein Structure, Tertiary; D059005:Topoisomerase II Inhibitors; D015003:Yeasts
D018943:Anthracyclines; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D004247:DNA; D004250:DNA Topoisomerases, Type II