207d

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SOLUTION STRUCTURE OF MITHRAMYCIN DIMERS BOUND TO PARTIALLY OVERLAPPING SITES ON DNA

Overview

Mithramycin (MTH) is a DNA-binding antitumor agent containing A-B, disaccharide and C-D-E trisaccharide segments projecting from opposite, ends of an aglycone chromophore. We have previously reported on the, solution structure of the MTH-DNA 6-mer complex based on a combined NMR, and molecular dynamics study. This study established that the, Mg(2+)-coordinated mithramycin dimer bound to a widened minor groove, centered about the sequence-specific (G-C).(G-C) site and that the C-D-E, trisaccharide segments from individual monomers were directed towards, opposite ends of the helix spanning a six base-pair segment. This research, is now extended to the binding of mithramycin dimers to partially, overlapping sites on the self-complementary d(T-A-G-C-T-A-G-C-T-A) 10-mer, duplex. The six base-pair mithramycin dimer footprint centered about, (G-C).(G-C) steps should result in a potential steric clash in the center, of the helix involving the inwardly pointing E-sugars of the pair of, mithramycin dimers bound to the DNA 10-mer duplex. The, MTH-d(T-A-G-C-T-A-G-C-T-A) complex (two MTH dimers per duplex) yields, narrow and well-resolved NMR spectra, which have been assigned to identify, intramolecular and intermolecular nuclear Overhauser enhancement (NOE), connectivities in the complex. The solution structure of the MTH-DNA, 10-mer complex based on distance-restrained molecular dynamics, calculations has defined the conformation of the drug and the DNA, necessary for accommodation of the pair of mithramycin dimers on the DNA, 10-mer helix. Specifically, the inwardly pointing E-sugars retain their, face-down alignment towards the floor of the minor groove and occupy, adjacent binding sites in the center of the duplex. This is achieved, in, part, through torsion angle differences in the glycosidic linkage bonds, along the length of the inwardly pointing aglycone-C-D-E trisaccharide, segment relative to its outwardly pointing aglycone-C-D-E trisaccharide, counterpart in the complex. In addition, a pronounced kink at the central, (T-A).(T-A) step opens the minor groove and generates additional space to, accommodate the inwardly pointing E-sugars at adjacent sites in the, MTH-DNA 10-mer complex. These studies establish conformational plasticity, in the C-D-E trisaccharide segment of the mithramycin dimer and, deformability of the DNA helix allowing mithramycin dimers to bind to, partially overlapping minor groove sites on the DNA helix.

About this Structure

207D is a Protein complex structure of sequences from [1] with , and as ligands. Full crystallographic information is available from OCA.

Reference

Solution structure of mithramycin dimers bound to partially overlapping sites on DNA., Sastry M, Fiala R, Patel DJ, J Mol Biol. 1995 Sep 1;251(5):674-89. PMID:7666419

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