An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach
Copyright policy )An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach
Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.
- Technical University of Munich Germany
- Eindhoven University of Technology Netherlands
- University of Dundee United Kingdom
- Technical University Eindhoven Netherlands
/dk/atira/pure/subjectarea/asjc/1300/1313, Molecular Structure, Escherichia coli Proteins, Transcription Factor RelA, 610, 540, Small Molecule Libraries, Structure-Activity Relationship, 14-3-3 Proteins, Benzaldehydes, Drug Design, name=Molecular Medicine, Escherichia coli, /dk/atira/pure/subjectarea/asjc/3000/3002, name=Drug Discovery, Protein Binding
/dk/atira/pure/subjectarea/asjc/1300/1313, Molecular Structure, Escherichia coli Proteins, Transcription Factor RelA, 610, 540, Small Molecule Libraries, Structure-Activity Relationship, 14-3-3 Proteins, Benzaldehydes, Drug Design, name=Molecular Medicine, Escherichia coli, /dk/atira/pure/subjectarea/asjc/3000/3002, name=Drug Discovery, Protein Binding
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