The three‐dimensional structure of the 4:1 mithramycin:d(ACCCGGGT) 2 complex: Evidence for an interaction between the E saccharides

Mithramycin and chromomycin, two antitumor drugs, each having an identical aglycone and nearly identical disaccharide and trisaccharide side chains, have differing binding properties to a small oligonucleotide, d(ACCCGGGT) 2 (M. A. Keniry et al., Journal of Molecular Biology, 1993, Vol. 231, pp. 753–767). In order to understand the forces that induce four mithramycin molecules to bind to d(ACCCGGGT) 2 instead of two drug molecules in the case of chromomycin, the structure of the 4:2:1 mithramycin: Mg 2+ :d(ACCCGGGT) 2 complex was investigated by 1 H‐nmr and restrained molecular dynamics. The resulting three‐dimensional model showed that in order to accommodate the close approach of one neighboring mithramycin dimer, the inwardly directed CDE saccharide chain of the neighboring mithramycin dimer undergoes a conformational change such that the E saccharide no longer spans the minor groove but reorients so that the hydrophilic face of the E saccharides from the two dimers oppose each other. Two hydrogen bonds are formed between the hydroxyl groups of the two opposing E saccharide groups. The results are interpreted in terms of the differences in stereochemistry and functional group substitutions between mithramycin and chromomycin. A mithramycin dimer is able to self‐associate on an oligonucleotide template because it has two hydroxyl groups on the same face of its terminal E saccharide. A chromomycin dimer is unable to self‐associate because one of these hydroxyl groups is acetylated and the neighboring hydroxyl group has a stereochemistry that cannot permit close contact of the hydroxyl group with a neighbouring chromomycin dimer.© 2000 John Wiley & Sons, Inc. Biopoly 54: 104–114, 2000