Allosteric Inhibition of Zinc-Finger Binding in the Major Groove of DNA by Minor-Groove Binding Ligands

Citations Over TimeTop 25% of 2004 papers

Abstract

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.

Related Papers

• → Unraveling Subunit Cooperativity in Homotetrameric HCN2 Channels(2012)16 cited
• → The spacing between binding sites controls the mode of cooperative DNA-protein interactions: implications for evolution of regulatory circuitry 1 1Edited by M. Gottesman(1998)24 cited
• → The multiple origins of cooperativity in binding to multi‐site lattices(1996)25 cited
• → Positive ion pair cooperativity exhibited for the binding of phosphate under physiological conditions(2005)20 cited
• → [17] Using analogs to study selectivity and cooperativity of cyclic nucleotide binding sites(1983)21 cited