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PDBsum entry 5h1v
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Transcription/transcription inhibitor
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PDB id
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5h1v
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References listed in PDB file
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Key reference
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Title
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The polar warhead of a trim24 bromodomain inhibitor rearranges a water-Mediated interaction network.
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Authors
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J.Liu,
F.Li,
H.Bao,
Y.Jiang,
S.Zhang,
R.Ma,
J.Gao,
J.Wu,
K.Ruan.
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Ref.
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Febs J, 2017,
284,
1082-1095.
[DOI no: ]
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PubMed id
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Abstract
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Tripartite motif-containing protein 24 (TRIM24) is closely correlated with
multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24
is essential for the proliferation of lethal castration-resistant prostate
cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using
NMR fragment-based screening. The crystal structures of two new inhibitors in
complex with the TRIM24 bromodomain reveal that the water-bridged interaction
network is conserved in the same fashion as those for known benzoimidazolone
inhibitors. Interestingly, the polar substitution on the warhead of one new
inhibitor pulls the whole ligand approximately 2 Å into the inner side pocket
of the TRIM24 bromodomain, and thus exhibits a binding mode significantly
different from other known bromodomain ligands. This mode provides a useful
handle for further hit-to-lead evolution toward novel inhibitors of the TRIM24
bromodomain.
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