Crystal structure of inhibitor of κB kinase β.
Publication Type:Journal Article
Source:Nature, Volume 472, Issue 7343, p.325-30 (2011)
Keywords:Amino Acid Motifs, Animals, Biocatalysis, Crystallography, X-Ray, Enzyme Activation, Humans, I-kappa B Kinase, Models, Molecular, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Substrate Specificity, Ubiquitin, Xenopus laevis
<p>Inhibitor of κB (IκB) kinase (IKK) phosphorylates IκB proteins, leading to their degradation and the liberation of nuclear factor κB for gene transcription. Here we report the crystal structure of IKKβ in complex with an inhibitor, at a resolution of 3.6 Å. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, α-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix-loop-helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with IκBα that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKKβ dimerization, but dimerization per se is not important for maintaining IKKβ activity and instead is required for IKKβ activation. Other IKK family members, IKKα, TBK1 and IKK-i, may have a similar trimodular architecture and function.</p>