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PDBsum entry 2r2u
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Transferase/DNA
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PDB id
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2r2u
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References listed in PDB file
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Key reference
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Title
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Crystal structure of DNA-Bound co(III) bleomycin b2: insights on intercalation and minor groove binding.
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Authors
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K.D.Goodwin,
M.A.Lewis,
E.C.Long,
M.M.Georgiadis.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
5052-5056.
[DOI no: ]
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PubMed id
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Abstract
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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 B(2). 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 beta 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.
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Figure 4.
Interactions of the bithiazole/C-terminal tail and linker
with the DNA. (A) Stereodiagram of 1 with DNA (gray) and
intercalated bithiazole/C-terminal tail (blue) and linker (red)
as a ball-and-stick model with waters (magenta) that contribute
to bithiazole/C-terminal tail positioning. Hydrogen bonds
represented as black dashed lines. Oxygen atoms in red (DNA) or
pink (BLM) and nitrogen atoms in blue (DNA) or cyan
(Co·BLM) are involved in H-bonding. Sulfur atoms are
yellow. (B) Superimposed 1 (gray) and 2 (black) 5′-GTT sites
with intercalated bithiazole/C-terminal tails (1, blue; 2,
orange) and relevant water from 1 (magenta) (rmsd of 5′-GT
base pairs = 0.54 Å).
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Figure 5.
Interactions of the metal-binding domain and disaccharide
with the DNA. (A) Stereodiagram of the minor groove of DNA
(gray) shown with the metal-binding (yellow with Co in green)
and disaccharide (purple) domains and a modeled peroxide ligand
(cyan) as a ball-and-stick model. Hydrogen bonds are represented
as dashed lines with interacting O atoms in red and N atoms in
blue. Intermolecular bonds are black, intramolecular bonds are
blue, and magenta bonds represent interactions of the
propionamide as modeled (the propioanamide is absent in electron
density). The red stick indicates the connection to the linker
domain. (B) Schematic showing the hydrogen-bonding interactions
of the metal-binding and disaccharide domains in the minor
groove with bonds colored as in A.
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