Structural basis of DNA recognition by anticancer antibiotics, chromomycinA(3), and mithramycin: Roles of minor groove width and ligand flexibility

Anticancer antibiotics, chromomycin A(3) (CHR) and mithramycin (MTR), inhib it cellular processes like transcription and replication, by binding revers ibly to double-stranded DNA via minor groove, in the presence of bivalent m etal ions like, 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)Mg2 + and DNA. For the purpose we have employed three synthetic oligonucleotide s with minor groove width lying between B- and A-type structures as model D NA sequences: d(GCGCGCGC)(2) in B-form, d(CCGGCGCCGG)(2) in B-form with unu sual wide minor groove, and (GGGGCCCC)(2) in A-form. Association of the (dr ug)(2)Mg2+ with the oligomers have been probed using spectroscopic techniqu es like absorbance, fluorescence, and CD. The binding and thermodynamic par ameters for the different association processes have also been characterize d. 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)Mg2+ an d (CHR)(2)Mg2+, has been observed that leads to differences in the energeti cs of recognition of the same DNA sequence by the two ligands. In contrast to (CHR)(2)Mg2+, higher flexibility in (MTR)(2)Mg2+ makes its conformation in the DNA bound form less sensitive to the groove dimension of DNA. (C) 20 01 John Wiley & Sons, Inc.