8DW1

Crystal structure of a host-guest complex with 5'-CTTAGTTATAACTAAG-3'

Summary for 8DW1

• Entry DOI: 10.2210/pdb8dw1/pdb
• Descriptor: reverse transcriptase, DNA (5'-D(*CP*TP*TP*AP*GP*TP*TP*A)-3'), DNA (5'-D(P*TP*AP*AP*CP*TP*AP*AP*G)-3'), ... (4 entities in total)
• Functional Keywords: host-guest complex dna structure b-form dna moloney murine leukemia virus reverse transcriptase, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Moloney murine leukemia virus; More
• Total number of polymer chains: 3
• Total formula weight: 34874.79

Authors

Georgiadis, M.M. (deposition date: 2022-07-30, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

Goodwin, K.D.,Lewis, M.A.,Long, E.C.,Georgiadis, M.M.
Two distinct rotations of bithiazole DNA intercalation revealed by direct comparison of crystal structures of Co(III)•bleomycin A 2 and B 2 bound to duplex 5'-TAGTT sites.
Bioorg.Med.Chem., 77:117113-117113, 2023

PubMed 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)•BLMA "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)•BLMA into preformed host-guest crystals including a preferred DNA-binding site. While the overall structure of DNA-bound BLMA was found to be similar to those reported earlier at the same DNA site for BLMB, the intercalated bithiazole of BLMB is "flipped" 180˚ relative to DNA-bound BLMA. 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.

PubMed: 36516684
DOI: 10.1016/j.bmc.2022.117113

Experimental method

X-RAY DIFFRACTION (1.849 Å)