Crystal structure of trioxacarcin A covalently bound to DNA
نویسندگان
چکیده
We report a crystal structure that shows an antibiotic that extracts a nucleobase from a DNA molecule 'caught in the act' after forming a covalent bond but before departing with the base. The structure of trioxacarcin A covalently bound to double-stranded d(AACCGGTT) was determined to 1.78 A resolution by MAD phasing employing brominated oligonucleotides. The DNA-drug complex has a unique structure that combines alkylation (at the N7 position of a guanine), intercalation (on the 3'-side of the alkylated guanine), and base flip-out. An antibiotic-induced flipping-out of a single, nonterminal nucleobase from a DNA duplex was observed for the first time in a crystal structure.
منابع مشابه
Crystalline guanine adducts of natural and synthetic trioxacarcins suggest a common biological mechanism and reveal a basis for the instability of trioxacarcin A.
X-ray crystallographic characterization of products derived from natural and fully synthetic trioxacarcins, molecules with potent antiproliferative effects, illuminates aspects of their reactivity and mechanism of action. Incubation of the fully synthetic trioxacarcin analog 3, which lacks one of the carbohydrate residues present in the natural product trioxacarcin A (1) as well as oxygenation ...
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