1fja

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NMR STUDY OF DEOXYRIBONUCLEIC ACID COMPLEXED WITH ACTINOMYCIN D

Overview

Actinomycin D (ActD) is a potent anti-tumor antibiotic, that, preferentially targets (G-C).(G-C) steps on duplex DNA. We have reported, on the solution structure of the ActD-d(A-A-A-G-C-T-T-T) complex (one drug, per duplex) based on a combined application of NMR and molecular dynamics, calculations. This study established that ActD binds to DNA through, intercalation of the phenoxazone chromophore between (G-C).(G-C) steps, with the benzenoid and quinonoid-linked cyclic pentapeptide lactone rings, spanning two base-pairs in opposite directions in the minor groove of the, helix. This research is now extended to the binding of two ActD molecules, to adjacent complexation sites within a (G-C-G-C).(G-C-G-C) segment in the, self-complementary d(A1-A2-G3-C4-G5-C6-T7-T8) duplex. The occupation of, the central (C4-G5).(C4-G5) segment between the two intercalation sites by, the inwardly pointing cyclic pentapeptide lactone rings from adjacent, bound ActD molecules should result in a potential steric clash in the, center of the helix. The NMR data and its analysis on the, ActD-d(A-A-G-C-G-C-T-T) complex (two drugs per duplex) establish that two, ActD molecules intercalate into symmetry-related (G3-C4).(G5-C6) steps, with their attached benzenoid and quinonoid cyclic pentapeptide lactone, rings positioned in the minor groove and directed towards the center and, the ends of the helix, respectively. The solution structure of the complex, was solved by using NMR restraints to guide distance geometry-simulated, annealing and restrained molecular dynamics calculations including, intensity-based refinements. The DNA helix exhibits a pronounced kink and, is fully unwound at the central (C4-G5).(C4-G5) step which results in an, opening and widening of the minor groove to generate additional space for, accommodation of the inwardly pointing benzenoid cyclic pentapeptide, lactone rings in the complex. The outwardly and inwardly pointing cyclic, pentapeptide lactone rings of symmetry-related ActD molecules retain, similar conformations with the largest difference observed for the L-MeVal, residues in the complex. The present study defines how structural changes, primarily in the DNA associated with the directional bending of the helix, towards the major groove and away from the bound drug opens up and widens, the minor groove to accommodate two intercalated ActD molecules bound at, partially overlapping sites on the DNA.

About this Structure

1FJA is a Protein complex structure of sequences from [1] with PXZ as ligand. Full crystallographic information is available from OCA.

Reference

DNA bending and unwinding associated with actinomycin D antibiotics bound to partially overlapping sites on DNA., Chen H, Liu X, Patel DJ, J Mol Biol. 1996 May 10;258(3):457-79. PMID:8642603

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