Crystal Structure of a Human IκB Kinase β Asymmetric Dimer

Phosphorylation of inhibitor of nuclear transcription factor kappa B (I kappa B) by I kappa B kinase (IKK) triggers the degradation of I kappa B and migration of cytoplasmic kappa B to the nucleus where it promotes the transcription of its target genes. Activation of IKK is achieved by phosphorylation of its main subunit, IKK beta, at the activation loop sites. Here, we report the 2.8 angstrom resolution crystal structure of human IKK beta (hIKK beta), which is partially phosphorylated and bound to the staurosporine analog K252a. The hIKK beta protomer adopts a trimodular structure that closely resembles that from Xenopus laevis (xIKK beta): an N-terminal kinase domain (KD), a central ubiquitin-like domain (ULD), and a C-terminal scaffold/dimerization domain (SDD). Although hIKK beta and xIKK beta utilize a similar dimerization mode, their overall geometries are distinct. In contrast to the structure resembling closed shears reported previously for xIKK beta, hIKK beta exists as an open asymmetric dimer in which the two KDs are further apart, with one in an active and the other in an inactive conformation. Dimer interactions are limited to the C-terminal six-helix bundle that acts as a hinge between the two subunits. The observed domain movements in the structures of IKK beta may represent trans-phosphorylation steps that accompany IKK beta activation.