AUROMOMYCIN: STRUCTURAL STUDY OF ANTICANCER ACTIVITY

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The antitumor antibiotic Auromomycin inhibits cell growth by causing single stand breaks in DNA. The drug is composed of a 12,000 molecular weight protein fragment, macromomycin, and a nonprotein chromophore which is the cytotoxic component. The apo-protein serves as a carrier and a regulator for the release of the chromophore. We are undertaking the crystal structure analysis of the apoprotein, the holoantibiotic, the chromophore and its complexes with DNA fragments in order to correlate the three-dimenstional structural features with the biological activity. The goal of this study is to determine unambigously: the chemical composition of the chromophore in active and inactive form; the nature of the binding of the chromophore to the apoprotein and the DNA; the amino acids and the chromophore groups involved in binding; and the relationship between binding of the chromophore to DNA, the instability of the chromophore and its strand scission activity. Furthermore, information regarding the interaction of the protein with the membrane such as identification of the amino acids that may be invovled in the binding to the cell membrane and the transfer of the protein or the chromophore across the membrane will be obtained. Comparison of the conformations of the holoantibiotic and the apoprotein may suggest possible mechanisms for the release of the chromophore. Combination of the results of these crystallographic studies with biochemical data will result in better understanding of the action of the anticancer agent, suggest chemcial modification to the apoprotein and the chromophore that might result in greater specificity and potency of action and aid in the development of proteins as potential cell specific drug delivery agents.