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. 2018 Aug 23;7(9):115. doi: 10.3390/cells7090115

Figure 3.

Figure 3

Insights from X-ray crystallographic studies of IKKβ. (A) Predicted allosteric binding site between the KD (yellow) and ULD (blue) of the catalytically inactive conformation of the human IKKβ monomer. Surface representation of residues surrounding the binding pocket is shown in magenta. SDD, green. Liu et al. identified a compound that specifically binds to this allosteric pocket in the inactive conformation of IKKβ, but not the active conformation, and blocks IKKβ activation. Figure adapted from [130] PDB ID: 4KIK. (B) Ribbon diagram of a human IKKβ dimer (chains A and F) in a catalytically active conformation taken from the asymmetric unit of the crystallographic structure. The primary dimer interface is mediated by residues of the C-terminal portion of the SDD (dashed box). Figure adapted from [6]. PDB ID: 4E3C. (C) Close-up view of the boxed area from panel B. Displayed are residues mediating interactions at the dimer SDD interface that have been shown to be important for IKKβ catalytic activity in vitro via site-directed mutagenesis. Three pairs of residues were mutated (W655D/L658D, L654D/W655D and K482A/F485D) and in vitro kinase assays with human IKKβ performed [6]. Figure adapted from [6]. PDB ID: 4E3C. (D) Ribbon diagram showing the interaction of neighbouring, symmetry-related tetrameric assemblies of IKKβ protomers within the crystal. This oligomerisation positions two KDs (from chains A, green, and D’, magenta, in the representation provided) within close proximity to one another (dashed box). Figure adapted from [6]. PDB ID: 4E3C. (E) Close-up view of the boxed area from panel D. The arrangement of neighbouring KDs (from A and D’) positions the kinase activation loop (shown in yellow and blue) of one protomer directly over the active site of its neighbour, and potentially facilitates oligomerization-dependent trans auto-phosphorylation. Activation loop E177 and E181 (mutant forms of WT S177 and S181) are shown in cyan and red, respectively. The Cα positions of V229 and H232 are marked as orange spheres. Mutation of these, and other residues mediating interactions at this KD-KD oligomerisation interface inhibited IKKβ catalytic activity and activation loop phosphorylation in vitro [6]. Figure adapted from [6]. PDB ID: 4E3C. Small molecules designed to interfere with dimerization/oligomerization via the interfaces shown in panel C and E may function as specific inhibitors of IKKβ. Figures were prepared using program PyMOL [131,132].