DNA microstructure influences selective binding of small molecules designed to target mixed-site DNA sequences

Laughlin-Toth, Sarah; Carter, E. Kathleen; Ivanov, Ivaylo; Wilson, W. David

doi:10.1093/nar/gkw1232

Title: DNA microstructure influences selective binding of small molecules designed to target mixed-site DNA sequences

Journal Article · Fri Dec 09 00:00:00 EST 2016 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkw1232· OSTI ID:1523833

^[1]; Carter, E. Kathleen ^[1]; Ivanov, Ivaylo ^[1]; Wilson, W. David ^[1]

Georgia State Univ., Atlanta, GA (United States)

Specific targeting of protein–nucleic acid interactions is an area of current interest, for example, in the regulation of gene-expression. Most transcription factor proteins bind in the DNA major groove; however, we are interested in an approach using small molecules to target the minor groove to control expression by an allosteric mechanism. In an effort to broaden sequence recognition of DNA-targeted-small-molecules to include both A·T and G·C base pairs, we recently discovered that the heterocyclic diamidine, DB2277, forms a strong monomer complex with a DNA sequence containing 5'-AAAGTTT-3'. Competition mass spectrometry and surface plasmon resonance identified new monomer complexes, as well as unexpected binding of two DB2277 with certain sequences. Inherent microstructural differences within the experimental DNAs were identified through computational analyses to understand the molecular basis for recognition. These findings emphasize the critical nature of the DNA minor groove microstructure for sequence-specific recognition and offer new avenues to design synthetic small molecules for effective regulation of gene-expression.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH1231

OSTI ID:: 1523833

Journal Information:: Nucleic Acids Research, Vol. 45, Issue 3; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 6 works

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