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Published July 16, 2003 | public
Journal Article

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

Abstract

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.

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.

Additional details

Created:
August 19, 2023
Modified:
October 18, 2023