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Cell Rep DOI:10.1016/j.celrep.2013.01.033

Structure and ubiquitination-dependent activation of TANK-binding kinase 1.

Publication TypeJournal Article
Year of Publication2013
AuthorsTu, D, Zhu, Z, Zhou, AY, Yun, C-H, Lee, K-E, Toms, AV, Li, Y, Dunn, GP, Chan, E, Thai, T, Yang, S, Ficarro, SB, Marto, JA, Jeon, H, Hahn, WC, Barbie, DA, Eck, MJ
JournalCell Rep
Date Published2013 Mar 28
KeywordsAmino Acid Sequence, Binding Sites, Crystallography, X-Ray, Humans, I-kappa B Kinase, Interferon Regulatory Factor-3, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Ubiquitination

Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) induces type I interferon expression and modulates nuclear factor κB (NF-κB) signaling. Here, we describe the 2.4 Å-resolution crystal structure of nearly full-length TBK1 in complex with specific inhibitors. The structure reveals a dimeric assembly created by an extensive network of interactions among the kinase, ubiquitin-like, and scaffold/dimerization domains. An intact TBK1 dimer undergoes K63-linked polyubiquitination on lysines 30 and 401, and these modifications are required for TBK1 activity. The ubiquitination sites and dimer contacts are conserved in the close homolog inhibitor of κB kinase ε (IKKε) but not in IKKβ, a canonical IKK that assembles in an unrelated manner. The multidomain architecture of TBK1 provides a structural platform for integrating ubiquitination with kinase activation and IRF3 phosphorylation. The structure of TBK1 will facilitate studies of the atypical IKKs in normal and disease physiology and further the development of more specific inhibitors that may be useful as anticancer or anti-inflammatory agents.


Alternate JournalCell Rep
PubMed ID23453972
PubMed Central IDPMC3863638
Grant ListR01 GM071834 / GM / NIGMS NIH HHS / United States
K01 CA094223 / CA / NCI NIH HHS / United States
K08 CA138918 / CA / NCI NIH HHS / United States
P01 CA117969 / CA / NCI NIH HHS / United States
R01 CA080942 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
K08 CA138918-01A1 / CA / NCI NIH HHS / United States