Figure 3.

Imidazole-benzaldehydes are stabilizing the p65_45/14-3-3 complex. (A) The imidazole moiety of 5 (teal sticks) offers three vectors for fragment growth (arrows) (PDB: 6YP3).²⁵ (B) Fragment induced p65_45/14-3-3γ ternary complex formation, measured with compound titrations in FA (r/mAU). The compounds were titrated to 50 μM 14-3-3γ and 100 nM p65_45. (C) Ternary structure of 16d (light blue sticks; PDB: 7NM9) binding to the p65_45/14-3-3σΔC complex. (D) Mixture of structural isomers of 16j and 16k. (E, F) Crystal structure of 16k binding to the p65_45/14-3-3σΔC complex (PDB: 7NR7). The electron density map indicates two binding poses (E). Based on the position of the methoxy substitution, the 2-chloro substitution points either toward the peptide (16k-5) or to the FC pocket (16k-6). Both binding poses engage in hydrophobic contacts with 14-3-3 and p65 (sphere representation, F). For all: 14-3-3: white cartoon, surface, sticks; p65_45: red sticks; 2Fo-Fc electron density map (contoured at 1σ): gray mesh.