Crystal structure of DNA-bound Co(III)·bleomycin B2: Insights on intercalation and minor groove binding

Kristie D. Goodwin, Mark A. Lewis, Eric C. Long, Millie Georgiadis

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Bleomycins constitute a widely studied class of complex DNA cleaving natural products that are used to treat various cancers. Since their first isolation, the bleomycins have provided a paradigm for the development and discovery of additional DNA-cleaving chemotherapeutic agents. The bleomycins consist of a disaccharide-modified metal-binding domain connected to a bithiazole/C-terminal tail via a methylvalerate-Thr linker and induce DNA damage after oxygen activation through site-selective cleavage of duplex DNA at 5′-GT/C sites. Here, we present crystal structures of two different 5′-GT containing oligonucleotides in both the presence and absence of bound Co(III)·bleomycin B2. Several findings from our studies impact the current view of bleomycin binding to DNA. First, we report that the bithiazole intercalates in two distinct modes and can do so independently of well ordered minor groove binding of the metal binding/disaccharide domains. Second, the Co(III)-coordinating equatorial ligands in our structure include the imidazole, histidine amide, pyrimidine N1, and the secondary amine of the β aminoalanine, whereas the primary amine acts as an axial ligand. Third, minor groove binding of Co(III)·bleomycin involves direct hydrogen bonding interactions of the metal binding domain and disaccharide with the DNA. Finally, modeling of a hydroperoxide ligand coordinated to Co(III) suggests that it is ideally positioned for initiation of C4′-H abstraction.

Original languageEnglish
Pages (from-to)5052-5056
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number13
DOIs
StatePublished - Apr 1 2008

Fingerprint

Bleomycin
Disaccharides
DNA
Metals
Ligands
Amines
DNA Cleavage
Hydrogen Bonding
Biological Products
Histidine
Amides
Oligonucleotides
Hydrogen Peroxide
DNA Damage
cobalt bleomycin
Oxygen
Neoplasms

Keywords

  • Antitumor
  • DNA-binding
  • HOO-Co(III) bleomycin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Crystal structure of DNA-bound Co(III)·bleomycin B2 : Insights on intercalation and minor groove binding. / Goodwin, Kristie D.; Lewis, Mark A.; Long, Eric C.; Georgiadis, Millie.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 13, 01.04.2008, p. 5052-5056.

Research output: Contribution to journalArticle

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