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PDBsum entry 1lwv
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Hydrolase/DNA
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PDB id
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1lwv
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Product-Assisted catalysis in base-Excision DNA repair.
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Authors
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J.C.Fromme,
S.D.Bruner,
W.Yang,
M.Karplus,
G.L.Verdine.
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Ref.
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Nat Struct Biol, 2003,
10,
204-211.
[DOI no: ]
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PubMed id
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Abstract
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Most spontaneous damage to bases in DNA is corrected through the action of the
base-excision DNA repair pathway. Base excision repair is initiated by DNA
glycosylases, lesion-specific enzymes that intercept aberrant bases in DNA and
catalyze their excision. How such proteins accomplish the feat of catalyzing no
fewer than five sequential reaction steps using a single active site has been
unknown. To help answer this, we report the structure of a trapped catalytic
intermediate in DNA repair by human 8-oxoguanine DNA glycosylase. This structure
and supporting biochemical results reveal that the enzyme sequesters the excised
lesion base and exploits it as a cofactor to participate in catalysis. To our
knowledge, the present example represents the first documented case of
product-assisted catalysis in an enzyme-catalyzed reaction.
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Figure 2.
Figure 2. Close-up view of the hOGG1 active site region. a,
Stereo view showing a  A^48-weighted
2F[o] - F[c] electron density map modeled at 1 ,
with elements of the protein and DNA in ball-and-stick models.
The oxoG is red; Lys249, purple; DNA, gold; and the C-N bond
between Lys249 of hOGG1 and C1' of the substrate, pink. b,
Least-squares superposition of the active site region of the
borohydride-trapped complex (same color scheme as in (a), except
side chains are shown in teal) with that of the recognition
complex with the K249Q mutation and an intact oxo-dG lesion21
(PDB entry 1EBM) (gray except Gln249, which is green).
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Figure 3.
Figure 3. Interactions of the sequestered oxoG base with other
components in the active site of the borohydride-trapped
complex. a, Ball-and-stick representation of the X-ray
structure. Color scheme is as in Fig. 2. b, Schematic depiction
of the oxoG triangulated in position over the three atoms that
are involved in acid/base chemistry during the  -lyase
cascade (N  ,
O4' and C2'). Hydrogen bonding interactions are denoted by
dashes. Dots indicate the distance between N9 and C2'. Note the
distances between the N9 of oxoG and the O4' of the substrate
sugar and the N of
Lys249 in (a), indicative of hydrogen-bonding interactions. Also
note the disposition of the proS and proR protons (denoted S and
R, respectively) on C2' with respect to N9 and O8. The helix
capping interaction between the side chain of Asp268 and the N
terminus of helix  M
is clearly visible in (a).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2003,
10,
204-211)
copyright 2003.
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