CRYSTAL-STRUCTURES OF THE SIDE-BY-SIDE BINDING OF DISTAMYCIN TO AT-CONTAINING DNA OCTAMERS D(ICITACIC) AND D(ICATATIC)

To understand the recognition interactions between AT-containing alter nating DNA and minor groove binding drugs, the crystal structures of t he side-by-side binding of two distamycin molecules to the DNA octamer s d(ICITACIC)(2) and d(ICATATIC)(2), referred to here as TA and ATAT, respectively, have been determined at 1.6 Angstrom and 2.2 Angstrom, r espectively. Compared to the previous 2:1 all-IC d(ICICICIC)(2) . dist amycin complex, the substitutions of the I . C base-pairs by the A . T base-pairs enable the interactions of the drug with its natural targe t to be studied. Both complexes assume side-by-side drug binding, isom orphous to the all IC counterpart in the tetragonal space group P4(1)2 2 (a = b = 28.03 Angstrom, c = 58.04 Angstrom and a = b = 27.86 Angstr om, c = 58.62 Angstrom, respectively). The ATAT complex also crystalli zed in a new polymorphic monoclinic space group C2 (a = 33.38 Angstrom , b = 25.33 Angstrom, c = 28.11 Angstrom and beta = 120.45 degrees) an d was solved at 1.9 Angstrom resolution. The structures of the three d ouble drug . DNA complexes are very similar, characterized by systemat ic hydrogen bonding and van der Waals interactions. Each drug hydrogen bonds with the bases of the proximal DNA strand only and stacks with the sugar moiety, while the side-by-side drugs themselves exhibit pyrr ole ring-peptide stacking. The pyrrole-peptide interaction is crucial for the side-by-side binding mode of the distamycin/netropsin family o f drugs. The purine-pyrimidine alternation is probably responsible for the striking alternation in the helical and backbone conformations. T he structures are conserved between the pure IC complex and the AT sub stituted complexes but further details of the side-by-side binding to DNA are provided by the 1.6 Angstrom resolution structure of TA. (C) 1 997 Academic Press Limited.