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PDBsum entry 6s3c
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Peptide binding protein
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PDB id
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6s3c
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References listed in PDB file
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Key reference
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Title
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Fragment-Based differential targeting of ppi stabilizer interfaces.
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Authors
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X.Guillory,
M.Wolter,
S.Leysen,
J.F.Neves,
A.Kuusk,
S.Genet,
B.Somsen,
J.K.Morrow,
E.Rivers,
L.Van beek,
J.Patel,
R.Goodnow,
H.Schoenherr,
N.Fuller,
Q.Cao,
R.G.Doveston,
L.Brunsveld,
M.R.Arkin,
P.Castaldi,
H.Boyd,
I.Landrieu,
H.Chen,
C.Ottmann.
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Ref.
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J Med Chem, 2020,
63,
6694-6707.
[DOI no: ]
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PubMed id
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Abstract
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Stabilization of protein-protein interactions (PPIs) holds great potential for
therapeutic agents, as illustrated by the successful drugs rapamycin and
lenalidomide. However, how such interface-binding molecules can be created in a
rational, bottom-up manner is a largely unanswered question. We report here how
a fragment-based approach can be used to identify chemical starting points for
the development of small-molecule stabilizers that differentiate between two
different PPI interfaces of the adapter protein 14-3-3. The fragments
discriminately bind to the interface of 14-3-3 with the recognition motif of
either the tumor suppressor protein p53 or the oncogenic transcription factor
TAZ. This X-ray crystallography driven study shows that the rim of the interface
of individual 14-3-3 complexes can be targeted in a differential manner with
fragments that represent promising starting points for the development of
specific 14-3-3 PPI stabilizers.
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