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 bis intercalate into DNA. Common features among these antibiotics include two heterocyclic aromatic ring systems propagating from a cross-bridge d cyclic octadepsipeptide scaffold. We report on the solution structur e of the QN-d(A1-C2-A3-C4-G5-T6-G7-T8) complex (one QN molecule per du plex) based on a combined NMR-molecular dynamics study including inten sity-based refinement. The S-hydroxy quinaldic acid rings bisintercala te into the duplex at (A3-C4).(G5-T6) steps and stack with flanking Wa tson-Crick A3.T6 and C4.G5 base-pairs. The intercalation sites at (A3- C4).(G5-T6) steps are wedge-shaped and unwound, with significant unwin ding also observed at the (C4-G5).(C4-G5) step bracketed between the i ntercalation sites. The cross-bridged cyclic octadepsipeptide is posit ioned in the minor groove with the methyl groups on its Ala and NMe-MC p residues directed towards and making van der Waals contacts with the minor groove edge of the duplex. A pair of adjacent intermolecular hy drogen bonds between the Ala backbone atoms and the G5 minor groove ed ge (Ala-NH to G5-N-(3) and G5-NH(2)e to Ala-CO) account for the sequen ce specificity associated with complex formation. The solution structu re of the QN-DNA oligomer complex, which contains only Watson-Crick ba se-pairs flanking the bisintercalation site, is compared with the crys tal structure of the related echinomycin-DNA oligomer complex, which c ontains Hoogsteen base-pairs on either side of the bisintercalation si te.