Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 132, Issue 49, Pages 17588-17598Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja107575f
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Funding
- NSF-MRI [0417731]
- San Diego Foundation
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0417731] Funding Source: National Science Foundation
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The solution structures of two different DNA duplexes (one containing a G-T mismatched base pair and the other a non-hydrogen-bonding G-F pair, where F is difluorotoluene) in complex with the peptide antibiotic actinomycin D (ActD) are presented. Using H-1, F-19 NMR, and molecular dynamics simulations, we show that there are three major differences between the complexes: (1) ActD binds to the GF duplex in an orientation that is flipped 180 degrees relative to its position in the GT duplex; (2) whereas the difluorotoluene moiety takes the typical anti glycosidic conformation in the free (uncomplexed) GF duplex, it takes the syn conformation in the GF:ActD complex; and (3) in GF:ActD, the difluorotoluene moiety is completely unstacked in the helix; however, the guanine of the G-F pair is stacked quite well with the ActD intercalator and the flanking base on the 5' side. In GT:ActD, the G-T base pair (although pushed into the major groove from the non-Watson-Crick hydrogen-bonding pattern) stacks favorably with the ActD intercalator and the flanking base pair on the 5' side. The results described here indicate that a sequence-specific DNA binding ligand such as actinomycin D will, indeed, recognize and bind with high affinity to a DNA incorporating a non-natural, non-hydrogen-bonding nucleoside mimic despite the presentation of modified functionality in the binding site.
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