Crystal structure of inhibitorofkBkinase b

Inhibitor of kB (IkB) kinase (IKK) phosphorylates IkB proteins, leading to their degradation and the liberation of nuclear factorkB forgene transcription.Herewe report the crystal structure of IKKb in complexwith 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, a-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 IkBa that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDDmediates IKKb dimerization, but dimerization per se is not important for maintaining IKKb activity and instead is required for IKKb activation. Other IKK familymembers, IKKa, TBK1 and IKK-i,may have a similar trimodular architecture and function.