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J Biol Chem, Vol. 274, Issue 18, 12765-12773, April 30, 1999

Inhibition of Ets-1 DNA Binding and Ternary Complex Formation between Ets-1, NF-B, and DNA by a Designed DNA-binding Ligand

Liliane A. Dickinson, John W. Trauger^§, Eldon E. Baird^§, Peter B. Dervan^§, Barbara J. Graves^¶, and Joel M. Gottesfeld

From the  Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, the ^§ Division of Chemistry and Chemical Engineering and Beckman Institute, California Institute of Technology, Pasadena, California 91125, and the ^¶ Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah 84132

Sequence-specific pyrrole-imidazole polyamides can be designed to interfere with transcription factor binding and to regulate gene expression, both in vitro and in living cells. Polyamides bound adjacent to the recognition sites for TBP, Ets-1, and LEF-1 in the human immunodeficiency virus, type 1 (HIV-1), long terminal repeat inhibited transcription in cell-free assays and viral replication in human peripheral blood lymphocytes. The DNA binding activity of the transcription factor Ets-1 is specifically inhibited by a polyamide bound in the minor groove. Ets-1 is a member of the winged-helix-turn-helix family of transcription factors and binds DNA through a recognition helix bound in the major groove with additional phosphate contacts on either side of this major groove interaction. The inhibitory polyamide possibly interferes with phosphate contacts made by Ets-1, by occupying the adjacent minor groove. Full-length Ets-1 binds the HIV-1 enhancer through cooperative interactions with the p50 subunit of NF-B, and the Ets-inhibitory polyamide also blocks formation of ternary Ets-1·NF-B·DNA complexes on the HIV-1 enhancer. A polyamide bound adjacent to the recognition site for NF-B also inhibits NF-B binding and ternary complex formation. These results broaden the application range of minor groove-binding polyamides and demonstrate that these DNA ligands are powerful inhibitors of DNA-binding proteins that predominantly use major groove contacts and of cooperative protein-DNA ternary complexes.

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