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PDBsum entry 2hxm
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Complex of ung2 and a small molecule synthetic inhibitor
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Structure:
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Uracil-DNA glycosylase. Chain: a. Synonym: udg, ung2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ung, dgu, ung15. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.30Å
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R-factor:
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0.183
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R-free:
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0.206
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Authors:
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M.A.Bianchet,D.J.Krosky,S.Ghung,L.Seiple,L.M.Amzel,J.T.Stivers
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Key ref:
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D.J.Krosky
et al.
(2006).
Mimicking damaged DNA with a small molecule inhibitor of human UNG2.
Nucleic Acids Res,
34,
5872-5879.
PubMed id:
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Date:
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03-Aug-06
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Release date:
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05-Dec-06
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PROCHECK
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Headers
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References
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P13051
(UNG_HUMAN) -
Uracil-DNA glycosylase from Homo sapiens
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Seq:
Struc:
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313 a.a.
223 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Nucleic Acids Res
34:5872-5879
(2006)
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PubMed id:
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Mimicking damaged DNA with a small molecule inhibitor of human UNG2.
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D.J.Krosky,
M.A.Bianchet,
L.Seiple,
S.Chung,
L.M.Amzel,
J.T.Stivers.
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ABSTRACT
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Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that
is essential for a number of diverse biological phenomena ranging from antibody
diversification to B-cell lymphomas and type-1 human immunodeficiency virus
infectivity. During each of these processes, UNG2 recognizes uracilated DNA and
excises the uracil base by flipping it into the enzyme active site. We have
taken advantage of the extrahelical uracil recognition mechanism to build large
small-molecule libraries in which uracil is tethered via flexible alkane linkers
to a collection of secondary binding elements. This high-throughput synthesis
and screening approach produced two novel uracil-tethered inhibitors of UNG2,
the best of which was crystallized with the enzyme. Remarkably, this inhibitor
mimics the crucial hydrogen bonding and electrostatic interactions previously
observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of
the binding site selects for library ligands that share these DNA features. This
is a general approach to rapid discovery of inhibitors of enzymes that recognize
extrahelical damaged bases.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.O.Zharkov,
G.V.Mechetin,
and
G.A.Nevinsky
(2010).
Uracil-DNA glycosylase: Structural, thermodynamic and kinetic aspects of lesion search and recognition.
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Mutat Res,
685,
11-20.
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H.Huang,
J.T.Stivers,
and
M.M.Greenberg
(2009).
Competitive inhibition of uracil DNA glycosylase by a modified nucleotide whose triphosphate is a substrate for DNA polymerase.
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J Am Chem Soc,
131,
1344-1345.
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S.Chung,
J.B.Parker,
M.Bianchet,
L.M.Amzel,
and
J.T.Stivers
(2009).
Impact of linker strain and flexibility in the design of a fragment-based inhibitor.
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Nat Chem Biol,
5,
407-413.
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PDB codes:
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L.A.Seiple,
J.H.Cardellina,
R.Akee,
and
J.T.Stivers
(2008).
Potent inhibition of human apurinic/apyrimidinic endonuclease 1 by arylstibonic acids.
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Mol Pharmacol,
73,
669-677.
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Y.N.Weledji,
C.J.Wiederholt,
M.O.Delaney,
and
M.M.Greenberg
(2008).
DNA polymerase bypass in vitro and in E. coli of a C-nucleotide analogue of Fapy-dG.
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Bioorg Med Chem,
16,
4029-4034.
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H.S.Pettersen,
O.Sundheim,
K.M.Gilljam,
G.Slupphaug,
H.E.Krokan,
and
B.Kavli
(2007).
Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms.
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Nucleic Acids Res,
35,
3879-3892.
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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.
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Links
