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PDBsum entry 5epl
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Transcription/transcription inhibitor
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PDB id
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5epl
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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 cellular chemical probe targeting the chromodomains of polycomb repressive complex 1.
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Authors
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J.I.Stuckey,
B.M.Dickson,
N.Cheng,
Y.Liu,
J.L.Norris,
S.H.Cholensky,
W.Tempel,
S.Qin,
K.G.Huber,
C.Sagum,
K.Black,
F.Li,
X.P.Huang,
B.L.Roth,
B.M.Baughman,
G.Senisterra,
S.G.Pattenden,
M.Vedadi,
P.J.Brown,
M.T.Bedford,
J.Min,
C.H.Arrowsmith,
L.I.James,
S.V.Frye.
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Ref.
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Nat Chem Biol, 2016,
12,
180-187.
[DOI no: ]
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PubMed id
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Abstract
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We report the design and characterization of UNC3866, a potent antagonist of the
methyllysine (Kme) reading function of the Polycomb CBX and CDY families of
chromodomains. Polycomb CBX proteins regulate gene expression by targeting
Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their
chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently,
with a Kd of ∼100 nM for each, and is 6- to 18-fold selective as compared to
seven other CBX and CDY chromodomains while being highly selective over >250
other protein targets. X-ray crystallography revealed that UNC3866's
interactions with the CBX chromodomains closely mimic those of the methylated H3
tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate
that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform
dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell
proliferation, consistent with the known ability of CBX7 overexpression to
confer a growth advantage, whereas UNC4219, a methylated negative control
compound, has negligible effects.
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