Crystal structure of inhibitor of κB kinase β (IKKβ)

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 A. 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. IKK (inhibitor of κB kinase) is an important element in the activation of nuclear factor κB (NF-κB) transcription factors — master regulators of inflammatory, immune and apoptotic responses. Here Wu and colleagues describe the long awaited X-ray structure of a member of the IKK family in combination with an inhibitor. They show that IKKβ has a tri-molecular architecture that contains the kinase domain, a ubiquitin-like domain and an extended scaffolding and dimerization domain, and discuss the functional implications.