Fig. 4: Rational optimization of compound series enables selective stabilization of the 14-3-3/ChREBP complex. | Nature Communications

Fig. 4: Rational optimization of compound series enables selective stabilization of the 14-3-3/ChREBP complex.

From: Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions

Fig. 4

a Co-crystal structure of 14-3-3 and 12 binding in the phospho-accepting pocket. Front view of 14-3-3 monomer (white surface) and 12 (purple sticks). Final 2Fo–Fc electron density (blue mesh, contoured at 1.0σ) displayed for 12. The panel shows the surrounding amino acid side chains of 14-3-3 (white sticks) and the interactions between 12 and 14-3-3 (black dashed lines). b Crystallographic overlay of 12 (purple sticks) binding to 14-3-3, and 3 (blue sticks) binding to the 14-3-3/ChREBP binary complex. c Binding curves of 100 nM fluorescently-labeled ChREBP peptide titrated with 14-3-3β in the presence of 100 μM ligands (3, 30, or 26). Fold stabilization of the protein–protein interaction binding affinity depicted (green arrow). d Molecular switch evolution series, starting from PPI inhibitory activity for 11 and 12 (left) toward selective PPI stabilization for 3, 30, and 26 (right), as observed from titration data for 14-3-3β (2 μM) and several client-derived peptides (100 nM) each titrated with the compounds. Data and error bars represent mean ± SEM, n = 3 replicates. Source data are provided as a Source data file.

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