Two distinct rotations of bithiazole DNA intercalation revealed by direct comparison of crystal structures of Co(III)â¢bleomycin A2 and B2 bound to duplex 5'-TAGTT sites.
Bioorg Med Chem
; 77: 117113, 2023 01 01.
Article
in En
| MEDLINE
| ID: mdl-36516684
ABSTRACT
Bleomycins constitute a family of anticancer natural products that bind DNA through intercalation of a C-terminal tail/bithiazole moiety and hydrogen-bonding interactions between the remainder of the drug and the minor groove. The clinical utility of the bleomycins is believed to result from single- and double-strand DNA cleavage mediated by the HOO-Fe(III) form of the drug. The bleomycins also serve as a model system to understand the nature of complex drug-DNA interactions that may guide future DNA-targeted drug discovery. In this study, the impact of the C-terminal tail on bleomycin-DNA interactions was investigated. Toward this goal, we determined two crystal structures of HOO-Co(III)â¢BLMA2 "green" (a stable structural analogue of the active HOO-Fe(III) drug) bound to duplex DNA containing 5'-TAGTT, one in which the entire drug is bound (fully bound) and a second with only the C-terminal tail/bithiazole bound (partially bound). The structures reported here were captured by soaking HOO-Co(III)â¢BLMA2 into preformed host-guest crystals including a preferred DNA-binding site. While the overall structure of DNA-bound BLMA2 was found to be similar to those reported earlier at the same DNA site for BLMB2, the intercalated bithiazole of BLMB2 is "flipped" 180Ë relative to DNA-bound BLMA2. This finding highlights an unidentified role for the C-terminal tail in directing the intercalation of the bithiazole. In addition, these analyses identified specific bond rotations within the C-terminal domain of the drug that may be relevant for its reorganization and ability to carry out a double-strand DNA cleavage event.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bleomycin
/
Ferric Compounds
Type of study:
Prognostic_studies
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2023
Type:
Article
Affiliation country:
United States