Abstract
(+)‐CC ‐1065 is biologically potent DNA‐reactive antitumor antibiotic produced by Streptomyces zelensis. This antibiotic covalently modifies DNA by alkylation of N‐3 of a adenine in the minor groove. As a Structural consequence of covalent modification of DNA, the helix axis id 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 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 of (+)‐CC‐1065 entrapped/induced bending of DNA as a probe for the Sp1‐induced bending of the 21‐base‐pair repeat an Mu transpose bending of the att L3 sequence is described.