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PDBsum entry 6hkf
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Protein binding
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PDB id
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6hkf
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References listed in PDB file
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Key reference
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Title
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Site-Directed fragment-Based screening for the discovery of protein-Protein interaction stabilizers.
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Authors
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E.Sijbesma,
K.K.Hallenbeck,
S.Leysen,
P.J.De vink,
L.Skóra,
W.Jahnke,
L.Brunsveld,
M.R.Arkin,
C.Ottmann.
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Ref.
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J Am Chem Soc, 2019,
141,
3524-3531.
[DOI no: ]
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PubMed id
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Abstract
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Modulation of protein-protein interactions (PPIs) by small molecules has emerged
as a valuable approach in drug discovery. Compared to direct inhibition, PPI
stabilization is vastly underexplored but has strong advantages, including the
ability to gain selectivity by targeting an interface formed only upon
association of proteins. Here, we present the application of a site-directed
screening technique based on disulfide trapping (tethering) to select for
fragments that enhance the affinity between protein partners. We target the
phosphorylation-dependent interaction between the hub protein 14-3-3σ and a
peptide derived from Estrogen Receptor α (ERα), an important breast cancer
target that is negatively regulated by 14-3-3σ. We identify orthosteric
stabilizers that increase 14-3-3/ERα affinity up to 40-fold and propose the
mechanism of stabilization based on X-ray crystal structures. These fragments
already display partial selectivity toward ERα-like motifs over other
representative 14-3-3 clients. This first of its kind study illustrates the
potential of the tethering approach to overcome the hurdles in systematic PPI
stabilizer discovery.
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