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PDBsum entry 6yow
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Peptide binding protein
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PDB id
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6yow
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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 stabilizers of protein-Protein interactions through imine-Based tethering.
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Authors
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M.Wolter,
D.Valenti,
P.J.Cossar,
L.M.Levy,
S.Hristeva,
T.Genski,
T.Hoffmann,
L.Brunsveld,
D.Tzalis,
C.Ottmann.
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Ref.
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Angew Chem Int Ed Engl, 2020,
59,
21520-21524.
[DOI no: ]
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PubMed id
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Abstract
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Small-molecule stabilization of protein-protein interactions (PPIs) is a
promising concept in drug discovery, however the question how to identify or
design chemical starting points in a "bottom-up" approach is largely
unanswered. We report a novel concept for identifying initial chemical matter
for PPI stabilization based on imine-forming fragments. The imine bond offers a
covalent anchor for site-directed fragment targeting, whereas its transient
nature enables efficient analysis of structure-activity relationships. This bond
enables fragment identification and optimisation using protein crystallography.
We report novel fragments that bind specifically to a lysine at the PPI
interface of the p65-subunit-derived peptide of NF-κB with the adapter protein
14-3-3. Those fragments that subsequently establish contacts with the
p65-derived peptide, rather than with 14-3-3, efficiently stabilize the
14-3-3/p65 complex and offer novel starting points for molecular glues.
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