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PDBsum entry 6tjm
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Signaling protein
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PDB id
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6tjm
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References listed in PDB file
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Key reference
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Title
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Design of drug-Like protein-Protein interaction stabilizers guided by chelation-Controlled bioactive conformation stabilization.
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Authors
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F.Bosica,
S.A.Andrei,
J.F.Neves,
P.Brandt,
A.Gunnarsson,
I.Landrieu,
C.Ottmann,
G.O'Mahony.
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Ref.
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Chemistry, 2020,
26,
7131-7139.
[DOI no: ]
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PubMed id
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Abstract
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Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for
studying PPI stabilization. The complex natural product Fusicoccin A
stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies,
motivating the search for more drug-like chemical matter. However, drug-like
14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray
crystal structure of a PPI in complex with an extremely low potency stabilizer
uncovered an unexpected non-protein interacting, ligand-chelated Mg2+
leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization
potency. This originates from a novel chelation-controlled bioactive
conformation stabilization effect. Metal chelation has been associated with
pan-assay interference compounds (PAINS) and frequent hitter behavior, but
chelation can evidently also lead to true potency gains and find use as a
medicinal chemistry strategy to guide compound optimization. To demonstrate
this, we exploited the effect to design the first potent, selective, and
drug-like 14-3-3 PPI stabilizers.
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