• L H Hurley and D Sun.
• Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin 78712.
• J. Mol. Recognit. 1994 Jun 1; 7 (2): 123-32.

Abstract(+)-CC-1065 is a biologically potent DNA-reactive antitumor antibiotic produced by Streptomyces zelensis. This antibiotic covalently modifies DNA by alkylation of N-3 of adenine in the minor groove. As a structural consequence of covalent modification of DNA, the helix axis is bent into the minor groove. The drug-induced bending of DNA has similarities to intrinsic A-tract bending and the 3' adenine of A-tracts shows a unique reactivity to alkylation by (+)-CC-1065. Upon covalent modification of A-tracts, the magnitude of bending is increased and the helix is stiffened. Using high-field NMR, hydroxyl-radical footprinting and gel electrophoresis, the molecular basis for the high reactivity of the bonding sequence 5'-AGTTA* (an asterisk indicates the covalent modification site) to (+)-CC-1065 has been shown to involve the inherent conformational flexibility of this sequence. Furthermore, these studies also demonstrate that after alkylation the drug-induced bending is focused over the TT region. By analogy with the junction bend model for A-tracts, a 'truncated junction bend model' is proposed for this structure. Last, the application (+)-CC-1065 entrapped/induced bending of DNA as a probe for the Sp1-induced bending of the 21-base-pair repeat and Mu transposase bending of the att L3 sequence is described.

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