@article{6a8fd2334aa742eb9b978e0a1b7b3e47,
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 {\aa}-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.",
author = "Daqi Tu and Zehua Zhu and Zhou, {Alicia Y.} and Yun, {Cai hong} and Lee, {Kyung Eun} and Toms, {Angela V.} and Yiqun Li and Dunn, {Gavin P.} and Edmond Chan and Tran Thai and Shenghong Yang and Ficarro, {Scott B.} and Marto, {Jarrod A.} and Hyesung Jeon and Hahn, {William C.} and Barbie, {David A.} and Eck, {Michael J.}",
note = "Funding Information: We thank Dr. Natalia Shapiro and Sir Philip Cohen (MRC Protein Phosphorylation Unit, University of Dundee, Scotland, UK) for synthesizing and sharing the MRT67307 used in this study. We thank Nathanael Gray for helpful discussions, and the staff of the NE-CAT beamline at the Advanced Photon Source, Argonne National Laboratory, for assistance with data collection and processing. This work was supported in part by NIH grants PO1 CA154303 (M.J.E. and W.C.H.), R01 CA130988 (W.C.H.), P01 CA117969 (W.C.H.), K08 CA138918-01A1 (D.A.B.), RO1 GM071834 (M.J.E.), and RO1 CA080942 (M.J.E.). H.J. acknowledges support from the intramural research program of the Korea Institute of Science and Technology. D.A.B. was supported by a V Scholar Grant from the V Foundation for Cancer Research. W.C.H. and M.J.E. are consultants for Novartis Pharmaceuticals. ",
year = "2013",
doi = "10.1016/j.celrep.2013.01.033",
language = "English",
volume = "3",
pages = "747--758",
journal = "Cell Reports",
issn = "2211-1247",
number = "3",
}