Structural basis of DNA recognition by anticancer antibiotics, chromomycin A3, and mithramycin: Roles of minor groove width and ligand flexibility

Anticancer antibiotics, chromomycin A(3) (CHR) and mithramycin (MTR), inhibit cellular processes like transcription and replication, by binding reversibly to double-stranded DNA via minor groove, in the presence of bivalent metal ions like Mg(2+) with GC base specificity. Here, we have attempted to assess the roles of two parameters-namely DNA groove dimension and flexibility of the ligand-in the structural recognition between the ligands, (drug)(2)Mg(2+) and DNA. For the purpose we have employed three synthetic oligonucleotides with minor groove width lying between B- and A-type structures as model DNA sequences: d(GCGCGCGC)(2) in B-form, d(CCGGCGCCGG)(2) in B-form with unusual wide minor groove, and (GGGGCCCC)(2) in A-form. Association of the (drug)(2)Mg(2+) with the oligomers have been probed using spectroscopic techniques like absorbance, fluorescence, and CD. The binding and thermodynamic parameters for the different association processes have also been characterized. Major conclusions from the above studies are as follows. Groove size of the oligomers influences the conformation of the bound ligand. A saccharide dependent variation in structural rigidity of the ligands, (MTR)(2)Mg(2+) and (CHR)(2)Mg(2+), has been observed that leads to differences in the energetics of recognition of the same DNA sequence by the two ligands. In contrast to (CHR)(2)Mg(2+), higher flexibility in (MTR)(2)Mg(2+) makes its conformation in the DNA bound form less sensitive to the groove dimension of DNA.