Solution structure of a two-base DNA bulge complexed with an enediyne cleaving analog.
Nucleic acid bulges have been implicated in a number of biological processes and are specific cleavage targets for the enediyne antitumor antibiotic neocarzinostatin chromophore in a base-catalyzed, radical-mediated reaction. The solution structure of the complex between an analog of the bulge-specific cleaving species and an oligodeoxynucleotide containing a two-base bulge was elucidated by nuclear magnetic resonance. An unusual binding mode involves major groove recognition by the drug 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 bulge nucleotide. This structure clarifies the mechanism of bulge recognition and cleavage by a drug and provides insight into the design of bulge-specific nucleic acid binding molecules.
Stassinopoulos
A
A
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ji
J
J
Gao
X
X
Goldberg
I H
IH
D001482:Base Composition; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D053281:Enediynes; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*; D009353:Zinostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
D053281:Enediynes; D009838:Oligodeoxyribonucleotides; C032372:neocarzinostatin chromophore; D004247:DNA; D009353:Zinostatin