Exploring
the p65/14-3-3 interface with imine forming fragments.
(A) Overview of the composite binding pocket of 14-3-3 and the p65_45
peptide (PDB: 6QHL).38 (B) Crystal structure of the NF-κB
subunit p65 (PDB: 1IKN,39 IκBα and p50 hidden for
clarity) with known phosphorylated serine residues Ser281 and Ser45
labeled. (C) Interface of the ternary complex of 1/p65_45/14-3-3
(PDB: 6YOW).25 Indicated are three subpockets (the roof of
14-3-3, the FC-binding pocket, and the deep binding pocket), which
can be exploited by fragment extension. Shown are 14-3-3 (white sticks,
surface and cartoon), p65_45 peptide (red sticks), and fragment 1 (cyan sticks). (D) Fragment hits based on X-crystallography
screening with benzaldehyde binding to Lys122 of 14-3-3.