Bleomycins (BLMs) were isolated over fifty years ago from Streptomyces verticillus and constitute a family of DNA cleaving natural products with clinical antitumor activity. The BLMs bind various metal ions in vitro (Cu, Fe, and Co, among others) and are believed to derive their ability to induce oxidative DNA cleavage in vivo in an Fe2+- and O2-dependent fashion. While much is known, our knowledge of several aspects of the BLM-DNA interaction remains incomplete, including the elucidation of possible alternative drug-DNA binding modes. Towards this end, we reported the first crystal structures of HOO-Co(III)-BLM B2 “green” bound to a DNA oligonucleotide. In the work presented here, new structures of BLM A2 (as HOO-Co(III)-BLM A2 “green”) bound to 5'-TAGTT sites will be presented along with a direct comparison to previous BLM B2 structures crystallized at the same DNA site. These new BLM A2 structures include two possible “snapshots” of BLM-DNA binding through observation of a partially DNA-bound structure and a fully bound structure. Interestingly, while the DNA general binding layouts of these two drug congeners were similar, this investigation revealed stable drug-DNA binding through two distinct, congener-dependent modes of bithiazole DNA intercalation that differ by a 180 degree rotation. The above thus suggests a more active role than originally thought for the C-terminal domain of BLM (dimethylsulfonium for BLM A2 and guanidinium for BLM B2) in driving the drug-DNA binding process.

Crystal structures of the anti-cancer metallopeptides bleomycin A2 vs. B2 bound to DNA: Observation of two completely different congener-dependent bithiazole insertions at the same 5'-TAGTT site

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