SOLUTION STRUCTURE OF A 2-BASE DNA BULGE COMPLEXED WITH AN ENEDIYNE CLEAVING ANALOG

Nucleic acid bulges have been implicated in a number of biological pro cesses and are specific cleavage targets for the enediyne antitumor an tibiotic neocarzinostatin chromophore in a base-catalyzed, radical-med iated reaction. The solution structure of the complex between an analo g of the bulge-specific cleaving species and an oligodeoxynucleotide c ontaining a two-base bulge was elucidated by nuclear magnetic resonanc e. An unusual binding mode involves major groove recognition by the dr ug carbohydrate unit and tight fitting of the wedge-shaped drug in the triangular prism pocket formed by the two looped-out bulge bases and the neighboring base pairs. The two drug rings mimic helical DNA bases , complementing the bent DNA structure. The putative abstracting drug radical is 2.2 +/- 0.1 angstroms from the pro-S H5' of the target bulg e nucleotide. This structure clarifies the mechanism of bulge recognit ion and cleavage by a drug and provides insight into the design of bul ge-specific nucleic acid binding molecules.