title: Crystal structure of inhibitor of κB kinase β.
abstract: 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.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Guozhou
authors.initials: G
authors.lastname: Xu
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Lo
authors.forename: Qiubai
authors.initials: Q
authors.lastname: Li
authors.forename: Gennaro
authors.initials: G
authors.lastname: Napolitano
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.forename: Michel
authors.initials: M
authors.lastname: Dreano
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D025801:Ubiquitin / Q000737:chemistry; D014982:Xenopus laevis
chemical_list: D025801:Ubiquitin; D051550:I-kappa B Kinase