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Allosteric inhibition of zinc-finger binding in the major groove of DNA by minor-groove binding ligands

Nguyen-Hackley, Doan H. and Ramm, Elizabeth and Taylor, Christina M. and Joung, J. Keith and Dervan, Peter B. and Pabo, Carl O. (2004) Allosteric inhibition of zinc-finger binding in the major groove of DNA by minor-groove binding ligands. Biochemistry, 43 (13). pp. 3880-3890. ISSN 0006-2960. doi:10.1021/bi030223c.

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In recent years, two methods have been developed that may eventually allow the targeted regulation of a broad repertoire of genes. The engineered protein strategy involves selecting Cys(2)His(2) zinc finger proteins that will recognize specific sites in the major groove of DNA. The small molecule approach utilizes pairing rules for pyrrole-imidazole polyamides that target specific sites in the minor groove. To understand how these two methods might complement each other, we have begun exploring how polyamides and zinc fingers interact when they bind the same site on opposite grooves of DNA. Although structural comparisons show no obvious source of van der Waals collisions, we have found a significant "negative cooperativity" when the two classes of compounds are directed to the overlapping sites. Examining available crystal structures suggests that this may reflect differences in the precise DNA conformation, especially with regard to width and depth of the grooves, that is preferred for binding. These results may give new insights into the structural requirements for zinc finger and polyamide binding and may eventually lead to the development of even more powerful and flexible schemes for regulating gene expression.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 American Chemical Society. Received October 15, 2003; Revised Manuscript Received January 14, 2004. Publication Date (Web): March 13, 2004. TATA_(ZF), NRE_(ZF), and p53_(ZF) zinc finger peptides were overexpressed, purified, and submitted from Scot A. Wolfe, Robert Grant, and Sandra Fay-Richard, respectively. The pET-21d expression vector transformed in BL21(DE3) was submitted by Bryan S. Wang. We thank Ezra Peisach for a critical reading of this manuscript, and we thank members of the Pabo lab for their support and useful discussions throughout the experimental process and writing of this manuscript.
Issue or Number:13
Record Number:CaltechAUTHORS:20160509-114915301
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Official Citation:Allosteric Inhibition of Zinc-Finger Binding in the Major Groove of DNA by Minor-Groove Binding Ligands Doan H. Nguyen-Hackley, Elizabeth Ramm, Christina M. Taylor, J. Keith Joung, Peter B. Dervan, and Carl O. Pabo Biochemistry 2004 43 (13), 3880-3890 DOI: 10.1021/bi030223c
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66773
Deposited By: Victoria Brennan
Deposited On:17 May 2016 23:58
Last Modified:11 Nov 2021 00:02

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