 |
PDBsum entry 1gj2
 |
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Biochemistry
40:5894-5905
(2001)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Solution structure of Co(III)-bleomycin-OOH bound to a phosphoglycolate lesion containing oligonucleotide: implications for bleomycin-induced double-strand DNA cleavage.
|
|
S.T.Hoehn,
H.D.Junker,
R.C.Bunt,
C.J.Turner,
J.Stubbe.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Bleomycin (BLM) is an antitumor antibiotic that is used clinically. Its major
cause of cytotoxicity is thought to be related to BLM's ability to cause
double-strand (ds) DNA cleavage. A single molecule of BLM appears to cleave both
strands of DNA in the presence of its required cofactors Fe(2+) and oxygen
without dissociating from the helix. A mechanism for this process has been
proposed based on a model structure of the hydroperoxide of Co(III)-BLM (CoBLM)
bound sequence-specifically to an intact duplex containing a GTAC site, a hot
spot for ds cleavage [Vanderwall, D. E., Lui, S. M., Wu, W., Turner, C. J.,
Kozarich, J. W., and Stubbe, J. (1997) Chem. Biol. 4, 373-387]. In this paper,
we present a structural model for the second cleavage event. Two-dimensional NMR
spectroscopy and molecular modeling were carried out to study CoBLM bound to
d(CCAAAGXACTGGG).d(CCCAGTACTTTGG), where X represents a 3'-phosphoglycolate
lesion next to a 5'-phosphate. Assignments of 729 NOEs, including 51 between the
drug and the DNA and 126 within the BLM molecule, have been made. These NOEs in
addition to 96 dihedral angle constraints have been used to obtain a
well-defined structural model for this complex. The model reveals that the
bithiazole tail is partially intercalated between the T19 and the A20 of the
duplex and that the metal binding domain is poised for abstraction of the T19
H4' in the minor groove. The modeling further reveals that the predominant
conformation of the bithiazole protons is trans. Two cis conformations of these
protons are also observed, and ROESY experiments provide evidence for
interconversion of all of these forms. The relationship of these observations to
the model for ds cleavage is presented.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
S.Ramakrishnan,
E.Suresh,
A.Riyasdeen,
M.A.Akbarsha,
and
M.Palaniandavar
(2011).
DNA binding, prominent DNA cleavage and efficient anticancer activities of tris(diimine)iron(II) complexes.
|
| |
Dalton Trans,
40,
3524-3536.
|
|
|
|
|
|
|
L.V.Liu,
C.B.Bell,
S.D.Wong,
S.A.Wilson,
Y.Kwak,
M.S.Chow,
J.Zhao,
K.O.Hodgson,
B.Hedman,
and
E.I.Solomon
(2010).
Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods.
|
| |
Proc Natl Acad Sci U S A,
107,
22419-22424.
|
|
|
|
|
|
|
J.Chen,
M.K.Ghorai,
G.Kenney,
and
J.Stubbe
(2008).
Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage.
|
| |
Nucleic Acids Res,
36,
3781-3790.
|
|
|
|
|
|
|
K.D.Goodwin,
M.A.Lewis,
E.C.Long,
and
M.M.Georgiadis
(2008).
Crystal structure of DNA-bound Co(III) bleomycin B2: Insights on intercalation and minor groove binding.
|
| |
Proc Natl Acad Sci U S A,
105,
5052-5056.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
M.S.Chow,
L.V.Liu,
and
E.I.Solomon
(2008).
Further insights into the mechanism of the reaction of activated bleomycin with DNA.
|
| |
Proc Natl Acad Sci U S A,
105,
13241-13245.
|
|
|
|
|
|
|
R.W.Sun,
D.L.Ma,
E.L.Wong,
and
C.M.Che
(2007).
Some uses of transition metal complexes as anti-cancer and anti-HIV agents.
|
| |
Dalton Trans,
(),
4884-4892.
|
|
|
|
|
|
|
E.L.Wong,
G.S.Fang,
C.M.Che,
and
N.Zhu
(2005).
Highly cytotoxic iron(II) complexes with pentadentate pyridyl ligands as a new class of anti-tumor agents.
|
| |
Chem Commun (Camb),
(),
4578-4580.
|
|
|
|
|
|
|
E.Baroni,
V.Viscardi,
H.Cartagena-Lirola,
G.Lucchini,
and
M.P.Longhese
(2004).
The functions of budding yeast Sae2 in the DNA damage response require Mec1- and Tel1-dependent phosphorylation.
|
| |
Mol Cell Biol,
24,
4151-4165.
|
|
|
|
|
|
|
J.Chen,
and
J.Stubbe
(2004).
Bleomycins: new methods will allow reinvestigation of old issues.
|
| |
Curr Opin Chem Biol,
8,
175-181.
|
|
|
|
|
|
|
L.J.Ming
(2003).
Structure and function of "metalloantibiotics".
|
| |
Med Res Rev,
23,
697-762.
|
|
|
|
|
|
|
H.D.Junker,
S.T.Hoehn,
R.C.Bunt,
V.Marathius,
J.Chen,
C.J.Turner,
and
J.Stubbe
(2002).
Synthesis, characterization and solution structure of tethered oligonucleotides containing an internal 3'-phosphoglycolate, 5'-phosphate gapped lesion.
|
| |
Nucleic Acids Res,
30,
5497-5508.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
M.Sugiyama,
and
T.Kumagai
(2002).
Molecular and structural biology of bleomycin and its resistance determinants.
|
| |
J Biosci Bioeng,
93,
105-116.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
|
|
Links
