1amd
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NMR STUDY OF DNA (5'-D(*TP*GP*TP*AP*CP*A)-3') SELF-COMPLEMENTARY DUPLEX COMPLEXED WITH A BIS-DAUNORUBICIN WP-652, MINIMIZED AVERAGE STRUCTURE
OverviewOverview
In the search for new generations of anthracycline drugs, lower cytotoxic, side effects and higher activity against resistant cancer cells are two, major goals. A new class of bis-intercalating anthracycline drugs has been, designed, synthesized, and shown to have promising activity against, multidrug-resistant cells. Two daunorubicins symmetrically linked together, via a p-xylenyl group, either at their N3' (compound WP631) or N4' sites, (compound WP652), exhibit extraordinary DNA binding affinities. We have, used high-resolution NRM studies to understand the DNA binding mode of, these two new bis-daunorubicin anticancer compounds. The structures of the, WP631-d(ACGTACGT)2 and the WP652-d(TGTACA)2 complexes have been determined, by NOE-restrained refinement. WP631 binds strongly to the, 5'-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated, between the two CpG sites at both ends of the hexanucleotide sequence. The, overall conformation of the WP631-d(CGTACG)2 part is remarkably similar to, the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG)2, as predicted previously [Gao, Y.-G., & Wang, A.H.H. (1996), J. Biomol., Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652, prefers the 5'-PyGTPu tetranucleotide sequence, with the aglycons, intercalated between the PypG and TpPu sites. The binding of WP652 to DNA, results in a severely distroted B-DNA duplex with the p-xylenyl tether, moiety significantly protruded away from the bottom of the minor groove., While WP652 in some ways behaves similarly to other anticancer, bis-intercalating antibiotics (e.g., triostine A and echinomycin), the, detailed interactions between those two classes of bis-intercalators are, quite different.
About this StructureAbout this Structure
1AMD is a Protein complex structure of sequences from [1] with BNR as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Binding of two novel bisdaunorubicins to DNA studied by NMR spectroscopy., Robinson H, Priebe W, Chaires JB, Wang AH, Biochemistry. 1997 Jul 22;36(29):8663-70. PMID:9289011
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