A Continuous Transition from A-DNA to B-DNA in the 1:1 Complex between Nogalamycin and the Hexamer dCCCGGG

Abstract

The antibiotic nogalamycin, a drug with high specificity for TG and CG steps in double-stranded DNA, has been crystallized as a 1:1 complex with the hexamer d(CCCGGG). The antibiotic is inserted at the central CG step of the duplex, with the two sugars oriented in the same direction and with strong interactions with the DNA within the grooves. The amino-glucose residue makes an integral part of a well defined major groove hydration network with van der Waals contacts and several strong hydrogen bonds to the duplex. The nogalose residue resides in the minor groove, making primarily van der Waals contacts. The single site allows an accurate molecular description of the intercalation, without perturbations from end effects observed previously. The local unwinding induced by nogalamycin is completely relaxed 2 base pairs away from the intercalation site. The two strands of the DNA show a continuous deformation from the A to the B form: 1) the cytosines toward the 5 end of the nogalomycin site in each strand have c3-endo conformations while 5 guanosines toward the 3 ends have c2-endo conformations; 2) within each strand, the phosphatephosphate distances increase in a continuous manner from 5.7 Å (A-form) to 7

Destabilizing effect of a fluorouracil extra base in a hybrid RNA duplex compared with bromo and chloro analogues

“…1). This style of packing is well documented in A-DNA and B-DNA structures in both the free and intercalated states (Gao et al, 1990;Timsit & Moras, 1994;Cruse et al, 1994Cruse et al, , 1996Carter et al, 1997) and is considered to be an important stabilizing effect in the building and stability of crystals.…”

Crystal structures of nucleic acids and their drug complexes

“…A complex with the sequence d(TGTACA) has shown the drug bound in the two high-affinity TpG sites, 116 and highlights the contribution of solvent-mediated contacts to the observed sequence selectivity of this drug. The complex between nogalamycin and the sequence d(CCCGGG) is notable 117 in that it uniquely shows a 1:1 anthracycline-duplex complex, with the one drug molecule bound at the central CpG site (Fig. 20).…”

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

“…In a complex with 5'-d(CCCGGG) 2 -3', the nogalose sugar was shown by X-ray crystallography to interact with the minor groove and the aminoglucose residue with the major groove. 8 A variety of physicochemical and biochemical techniques have been used to study the structures and sequence selectivity of daunomycin and nogalamycin complexes with duplex DNA. 1,9 The sequence selectivity of daunomycin is more complex than that of simple intercalators owing to the presence of the daunosamine sugar.…”