Tu, Daqi Zhu, Zehua Zhou, Alicia Y. Yun, Cai-hong Lee, Kyung-Eun Toms, Angela V. Li, Yiqun Dunn, Gavin P. Chan, Edmond Tran Thai Yang, Shenghong Ficarro, Scott B. Marto, Jarrod A. Jeon, Hyesung Hahn, William C. Barbie, David A. Eck, Michael J. 2024-01-20T13:00:44Z 2024-01-20T13:00:44Z 2021-09-01 2013-03 2211-1247 https://pubs.kist.re.kr/handle/201004/128307 Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) induces type I interferon expression and modulates nuclear factor kappa B (NF-kappa B) signaling. Here, we describe the 2.4 angstrom-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 kB kinase epsilon (IKK epsilon) but not in IKK beta, 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. English CELL PRESS NF-KAPPA-B INNATE IMMUNE-RESPONSE BREAST-CANCER ONCOGENE TUMOR-SUPPRESSOR CYLD IKK-RELATED KINASE CELL-TRANSFORMATION LIVER DEGENERATION I INTERFERON CROSS-TALK TBK1 Structure and Ubiquitination-Dependent Activation of TANK-Binding Kinase 1 Article 10.1016/j.celrep.2013.01.033 1 CELL REPORTS, v.3, no.3, pp.747 - 758 CELL REPORTS 3 3 747 758 scie scopus 000321896000019 2-s2.0-84875808591 Cell Biology Cell Biology Article NF-KAPPA-B INNATE IMMUNE-RESPONSE BREAST-CANCER ONCOGENE TUMOR-SUPPRESSOR CYLD IKK-RELATED KINASE CELL-TRANSFORMATION LIVER DEGENERATION I INTERFERON CROSS-TALK TBK1