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PDBsum entry 2hxm
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References listed in PDB file
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Key reference
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Title
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Mimicking damaged DNA with a small molecule inhibitor of human ung2.
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Authors
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D.J.Krosky,
M.A.Bianchet,
L.Seiple,
S.Chung,
L.M.Amzel,
J.T.Stivers.
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Ref.
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Nucleic Acids Res, 2006,
34,
5872-5879.
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PubMed id
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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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Secondary reference #1
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Title
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Uracil-Directed ligand tethering: an efficient strategy for uracil DNA glycosylase (ung) inhibitor development.
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Authors
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Y.L.Jiang,
D.J.Krosky,
L.Seiple,
J.T.Stivers.
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Ref.
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J Am Chem Soc, 2005,
127,
17412-17420.
[DOI no: ]
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PubMed id
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