	Chazin Home \| Ca-binding Protein DB \| Vanderbilt Home
	Research Description \| Publications \| Wisdom \| Search

Understanding Ligand-DNA Interactions at the Molecular Level.

The long-range goals of this research are to use the techniques of structural biology to interpret the physiological activity of DNA carcinogens and anticancer drugs that share a common mechanism of interference with DNA metabolism. The approach taken consists of NMR characterization followed by determination of three-dimensional solution structures and interpretation with the aid of molecular simulations and molecular graphics. Extensive interaction with synthetic organic chemists is imperative to success in these projects. Our current interests center on compounds that not only bind to, but also react with the DNA substrate, because such agents often exhibit exceptionally high biological potencies. Outstanding progress has been made in studies of the duocarmycin DNA alkylating agents. Very high resolution structures have been determined of (+) duocarmycin-SA, the unnatural (-) enantiomer, and derivatives lacking key functional groups, all bound to the same high affinity DNA duplex. Comparative analysis of these complexes has provided critical new evidence regarding the hypothesis that DNA binding-induced twist in the ligand (in situ activation) governs the reactivity profiles and unique biological properties observed for these extremely potent DNA alkylating agents.

Signal Transduction by EF-hand Calcium-Binding Proteins | Understanding Ligand-DNA Interactions at the Molecular Level | DNA Replication Recombination and Repair

last updated August 8, 2001 by Jonathan Sheehan