1r4e
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(New page: 200px<br /><applet load="1r4e" size="450" color="white" frame="true" align="right" spinBox="true" caption="1r4e" /> '''Solution structure of the Complex Formed bet...)
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Revision as of 19:59, 24 November 2007
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Solution structure of the Complex Formed between a Left-Handed Wedge-Shaped Spirocyclic Molecule and Bulged DNA
Overview
The solution structure of the complex formed between an oligonucleotide, containing a two-base bulge (5'-CACGCAGTTCGGAC.5'-GTCCGATGCGTG) and, ent-DDI, a designed synthetic agent, has been elucidated using, high-resolution NMR spectroscopy and restrained molecular dynamic, simulation. Ent-DDI is a left-handed wedge-shaped spirocyclic molecule, whose aglycone portion is an enantiomer of DDI, which mimics the, spirocyclic geometry of the natural product, NCSi-gb, formed by, base-catalyzed activation of the enediyne antibiotic neocarzinostatin. The, benzindanone moiety of ent-DDI intercalates between the A6.T21 and the, T9.A20 base pairs, overlapping with portions of the purine bases; the, dihydronaphthalenone moiety is positioned in the minor groove along the, G7-T8-T9 bulge sequence; and the aminoglycoside is in the middle of the, minor groove, approaching A20 of the nonbulged strand. This alignment of, ent-DDI along the DNA helical duplex is in the reverse direction to that, of DDI. The aminoglycoside moiety of ent-DDI is positioned in the 3', direction from the bulge region, whereas that of the DDI is positioned in, the 5' direction from the same site. This reverse binding orientation, within the bulge site is the natural consequence of the opposite, handedness imposed by the spirocyclic ring junction and permits the, aromatic ring systems of the two spirocyclic enantiomers access to the, bulge region. NMR and CD data indicate that the DNA in the DDI-bulged DNA, complex undergoes a larger conformational change upon complex formation in, comparison to the ent-DDI-bulged DNA, explaining the different binding, affinities of the two drugs to the bulged DNA. In addition, there are, different placements of the bulge bases in the helical duplex in the two, complexes. One bulge base (G7) stacks inside the helix, and the other one, (T8) is extrahelical in the DDI-bulged DNA complex, whereas both bulge, bases in the ent-DDI-bulged DNA complex prefer extrahelical positions for, drug binding. Elucidation of the detailed binding characteristics of the, synthetic spirocyclic enantiomers provides a rational basis for the design, of stereochemically controlled drugs for bulge binding sites.
About this Structure
1R4E is a Protein complex structure of sequences from [1] with DDI as ligand. Full crystallographic information is available from OCA.
Reference
Stereochemical control of small molecule binding to bulged DNA: comparison of structures of spirocyclic enantiomer-bulged DNA complexes., Hwang GS, Jones GB, Goldberg IH, Biochemistry. 2004 Jan 27;43(3):641-50. PMID:14730968
Page seeded by OCA on Sat Nov 24 22:06:32 2007
