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Allosteric inhibition of protein--DNA complexes by polyamide--intercalator conjugates

Fechter, Eric J. and Dervan, Peter B. (2003) Allosteric inhibition of protein--DNA complexes by polyamide--intercalator conjugates. Journal of the American Chemical Society, 125 (28). pp. 8476-8485. ISSN 0002-7863. doi:10.1021/ja030125e.

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The sequence-specific inhibition of essential protein-DNA contacts in the promoter of a gene is a central issue for the regulation of gene expression by chemical methods. Hairpin polyamides have been shown to inhibit protein-DNA complexes in some but not all cases. For example, polyamides co-occupy the same DNA sequence in the minor groove in the presence of major-groove binding bZip proteins. Four hairpin polyamide-acridine conjugates were synthesized and shown to bind the minor groove of DNA with high affinity in a sequence-specific manner. The polyamide-acridine conjugates were shown to unwind DNA (phi = 14-15 degrees), evidence for intercalation by the acridine moiety. Importantly, the polyamide-intercalator conjugates, which combine sequence-specific groove binding with proximal local unwinding, inhibit major-groove DNA binding by the GCN4 bZip protein. This class of DNA binding molecules creates a sequence-specific allosteric change in DNA structure and has the potential to be a general inhibitor of transcription factor binding independent of the specific protein-DNA structure.

Item Type:Article
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URLURL TypeDescription Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2003 American Chemical Society. Received February 21, 2003. Publication Date (Web): June 19, 2003. We are grateful to the National Institutes of Health (Grant 27681) for research support and a Research Service Award to E.J.F. We also thank the Ralph M. Parsons Foundation for a predoctoral fellowship to E.J.F.
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Issue or Number:28
Record Number:CaltechAUTHORS:20160510-080153390
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Official Citation:Allosteric Inhibition of Protein−DNA Complexes by Polyamide−Intercalator Conjugates Eric J. Fechter and Peter B. Dervan Journal of the American Chemical Society 2003 125 (28), 8476-8485 DOI: 10.1021/ja030125e
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66802
Deposited By: Victoria Brennan
Deposited On:17 May 2016 23:36
Last Modified:11 Nov 2021 00:03

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