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, h ave differing binding properties to a small oligonucleotide, d(ACCCGGGT)(2) (M. A. Keniry et al., Journal of Molecular Biology, 1993, Vol. 231, pp. 75 3-7671. In order to understand the forces that induce four mithramycin mole cules to bind to d(ACCCGGCT)(2) instead of two drug molecules in the case o f chromomycin, the structure of the 4:2:1 mithramycin: Mg2+:d(ACCCGGGT)(2) complex was investigated by H-1-nmr and restrained molecular dynamics. The resulting three-dimensional model showed that in order to accommodate the c lose approach of one neighboring mithramycin dimer, the inwardly directed C DE saccharide chain of the neighboring mithramycin dimer undergoes a confor mational 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 t wo dimers oppose each other. Two hydrogen bonds are formed between the hydr oxyl groups of the two opposing E saccharide groups. The results are interp reted in terms of the differences in stereochemistry and functional group s ubstitutions between mithramycin and chromomycin A mithramycin dimer is abl e to self-associate oil ail oligonucleotide template because it has two hyd roxyl groups on the same face of its terminal E saccharide. A chromomycin d imer is unable to self-associate because one of these hydroxyl groups is ac etylated and the neighboring hydroxyl group has a stereochemistry that cann ot permit close contact of the hydroxyl group with a neighbouring chromomyc in dimer. (C) 2000 John Wiley & Sons, Inc.