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PDBsum entry 4qev
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Transcription/transcription inhibitor
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PDB id
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4qev
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References listed in PDB file
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Key reference
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Title
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Chemical biology. A bump-And-Hole approach to engineer controlled selectivity of bet bromodomain chemical probes.
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Authors
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M.G.Baud,
E.Lin-Shiao,
T.Cardote,
C.Tallant,
A.Pschibul,
K.H.Chan,
M.Zengerle,
J.R.Garcia,
T.T.Kwan,
F.M.Ferguson,
A.Ciulli.
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Ref.
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Science, 2014,
346,
638-641.
[DOI no: ]
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PubMed id
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Abstract
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Small molecules are useful tools for probing the biological function and
therapeutic potential of individual proteins, but achieving selectivity is
challenging when the target protein shares structural domains with other
proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest
because of their roles in transcriptional regulation, epigenetics, and cancer.
The BET bromodomains (protein interaction modules that bind acetyl-lysine) have
been targeted by potent small-molecule inhibitors, but these inhibitors lack
selectivity for individual family members. We developed an ethyl derivative of
an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds
leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to
540-fold selectivity relative to wild-type bromodomains. Cell culture studies
showed that blockade of the first bromodomain alone is sufficient to displace a
specific BET protein, Brd4, from chromatin. Expansion of this approach could
help identify the individual roles of single BET proteins in human physiology
and disease.
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