title: Structure and ubiquitination-dependent activation of TANK-binding kinase 1.
abstract: 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.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Daqi
authors: D
authors: Tu
authors: Zehua
authors: Z
authors: Zhu
authors: Alicia Y
authors: AY
authors: Zhou
authors: Cai-hong
authors: CH
authors: Yun
authors: Kyung-Eun
authors: KE
authors: Lee
authors: Angela V
authors: AV
authors: Toms
authors: Yiqun
authors: Y
authors: Li
authors: Gavin P
authors: GP
authors: Dunn
authors: Edmond
authors: E
authors: Chan
authors: Tran
authors: T
authors: Thai
authors: Shenghong
authors: S
authors: Yang
authors: Scott B
authors: SB
authors: Ficarro
authors: Jarrod A
authors: JA
authors: Marto
authors: Hyesung
authors: H
authors: Jeon
authors: William C
authors: WC
authors: Hahn
authors: David A
authors: DA
authors: Barbie
authors: Michael J
authors: MJ
authors: Eck
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054875:Ubiquitination
chemical_list: D050838:Interferon Regulatory Factor-3; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase