Anthracycline-DNA interactions at unfavourable base-pair triplet-binding sites: structures of d(CGGCCG)/daunomycin and d(TGGCCA)/adriamycin complexes.
The structures of two hexanucleotide-anthracycline complexes d(CGGCCG)/daunomycin and d(TGGCCA)/adriamycin have been determined using single-crystal X-ray diffraction techniques. In both cases the anthracycline molecule is bound to non-preferred d(YGG) base-pair triplet sites. For both complexes the crystals are tetragonal and belong to the space group P4(1)2(1)2. Unit-cell dimensions are a = 28.07 (2), c = 53.35 (1) and a = 28.01 (1), c = 52.99 (1) A, respectively, and the asymmetric unit of both structures consists of one strand of DNA, one drug molecule and approximately 50 water molecules. For the d(CGGCCG) complex the refinement converged with an R factor of 0.21 for 1108 reflections with F >/= 2sigma(F) in the resolution range 7.0-1.9 A. For the complex involving d(TGGCCA) the final R value was 0.22 for 1475 reflections in the range 7.0-1.7 A with the same criterion for observed data. Both complexes are essentially isomorphous with related structures but differ in terms of the number of favourable van der Waals interactions of the amino sugars of the drug molecules with the DNA duplexes and the formation in the minor groove of heterodromic pentagonal arrangements of hydrogen bonds involving water molecules which link the amino sugars to the DNA. These differences in structure are used to rationalize the lack of affinity of daunomycin-type anthracyclines for d(YGG) and d(YGC) sites.
Department of Chemistry, University of Manchester, England.
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Leonard
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Hambley
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McAuley-Hecht
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Brown
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Hunter