Your browser doesn't support javascript.
loading
Two distinct rotations of bithiazole DNA intercalation revealed by direct comparison of crystal structures of Co(III)•bleomycin A2 and B2 bound to duplex 5'-TAGTT sites.
Goodwin, Kristie D; Lewis, Mark A; Long, Eric C; Georgiadis, Millie M.
Affiliation
  • Goodwin KD; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Lewis MA; Department of Chemistry & Chemical Biology, Indiana University-Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis, IN 46202, USA.
  • Long EC; Department of Chemistry & Chemical Biology, Indiana University-Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis, IN 46202, USA. Electronic address: eclong@iu.edu.
  • Georgiadis MM; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: mgeorgia@iu.edu.
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)•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)•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" 180˚ 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.
Subject(s)
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

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