(+)-CC-1065 as a probe for intrinsic and protein-induced bending of DNA.
(+)-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.
Hurley
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Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin 78712.
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D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D015335:Molecular Probes; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009713:Nucleotidyltransferases / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000737:chemistry; D016329:Sp1 Transcription Factor / Q000378:metabolism; D019895:Transposases
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D015335:Molecular Probes; D011089:Polydeoxyribonucleotides; D016329:Sp1 Transcription Factor; C018782:CC 1065; D004247:DNA; D009713:Nucleotidyltransferases; D019895:Transposases