Structural basis of DNA recognition by anticancer
antibiotics, chromomycin A(3), and mithramycin: roles of minor groove width and
ligand flexibility.
Chakrabarti S, Bhattacharyya D, Dasgupta D.
Biophysics Division, Saha Institute of Nuclear Physics, 37, Belgachia Road,
Kolkata 700 037, India.
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. Copyright 2001 John Wiley & Sons, Inc.
Biopolymers 56: 85-95, 2001
