Solution structure of a quinomycin bisintercalator-DNA complex.
The quinomycin antibiotic UK-63052 (designated QN) exhibits a chemical structure related to the antibiotic echinomycin which is known to bisintercalate into DNA. Common features among these antibiotics include two heterocyclic aromatic ring systems propagating from a cross-bridged cyclic octadepsipeptide scaffold. We report on the solution structure of the QN-d(A1-C2-A3-C4-G5-T6-G7-T8) complex (one QN molecule per duplex) based on a combined NMR-molecular dynamics study including intensity-based refinement. The 3-hydroxy quinaldic acid rings bisintercalate into the duplex at (A3-C4).(G5-T6) steps and stack with flanking Watson-Crick A3.T6 and C4.G5 base-pairs. The intercalation sites at (A3-C4).(G5-T6) steps are wedge-shaped and unwound, with significant unwinding also observed at the (C4-C5).(C4-G5) step bracketed between the intercalation sites. The cross-bridged cyclic octadepsipeptide is positioned in the minor groove with the methyl groups on its Ala and NMe-MCp residues directed towards and making van der Waals contacts with the minor groove edge of the duplex. A pair of adjacent intermolecular hydrogen bonds between the Ala backbone atoms and the G5 minor groove edge (Ala-NH to G5-N(3) and G5-NH2e to Ala-CO) account for the sequence specificity associated with complex formation. The solution structure of the QN-DNA oligomer complex, which contains only Watson-Crick base-pairs flanking the bisintercalation site, is compared with the crystal structure of the related echinomycin-DNA oligomer complex, which contains Hoogsteen base-pairs on either side of the bisintercalation site.
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032.
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D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003196:Computer Graphics; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004448:Echinomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000378:metabolism; D011522:Protons; D012995:Solubility
D000900:Anti-Bacterial Agents; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D011522:Protons; C010777:quinomycin; C059030:UK 63052; D004448:Echinomycin; D004247:DNA