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PDBsum entry 4cxx
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Oxidoreductase
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PDB id
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4cxx
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References listed in PDB file
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Key reference
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Title
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A strategy based on nucleotide specificity leads to a subfamily-Selective and cell-Active inhibitor of n6-Methyladenosine demethylase fto.
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Authors
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J.D.W.Toh,
L.Sun,
L.Z.M.Lau,
J.Tan,
J.J.A.Low,
C.W.Q.Tang,
E.J.Y.Cheong,
M.J.H.Tan,
Y.Chen,
W.Hong,
Y.G.Gao,
E.C.Y.Woon.
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Ref.
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Chem Sci, 2015,
6,
112-122.
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PubMed id
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Abstract
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The AlkB family of nucleic acid demethylases are of intense biological and
medical interest because of their roles in nucleic acid repair and epigenetic
modification. However their functional and molecular mechanisms are unclear,
hence, there is strong interest in developing selective inhibitors for them.
Here we report the identification of key residues within the nucleotide-binding
sites of the AlkB subfamilies that likely determine their substrate specificity.
We further provide proof of principle that a strategy exploiting these inherent
structural differences can enable selective and potent inhibition of the AlkB
subfamilies. This is demonstrated by the first report of a subfamily-selective
and cell-active FTO inhibitor 12. The distinct selectivity of 12
for FTO against other AlkB subfamilies and 2OG oxygenases shall be of
considerable interest with regards to its potential use as a functional probe.
The strategy outlined here is likely applicable to other AlkB subfamilies, and,
more widely, to other 2OG oxygenases.
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