4IM3

Structure of Tank-Binding Kinase 1

Summary for 4IM3

• Entry DOI: 10.2210/pdb4im3/pdb
• Related: 4IM0 4IM2
• Descriptor: Serine/threonine-protein kinase TBK1, N-(3-{[5-iodo-4-({3-[(thiophen-2-ylcarbonyl)amino]propyl}amino)pyrimidin-2-yl]amino}phenyl)pyrrolidine-1-carboxamide, MERCURY (II) ION, ... (4 entities in total)
• Functional Keywords: kinase, serine/threonine kinase, bx795, pcmnp, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 77814.93

Authors

Tu, D.,Eck, M.J. (deposition date: 2013-01-01, release date: 2013-03-06, Last modification date: 2024-02-28)

Primary citation

Tu, D.,Zhu, Z.,Zhou, A.Y.,Yun, C.H.,Lee, K.E.,Toms, A.V.,Li, Y.,Dunn, G.P.,Chan, E.,Thai, T.,Yang, S.,Ficarro, S.B.,Marto, J.A.,Jeon, H.,Hahn, W.C.,Barbie, D.A.,Eck, M.J.
Structure and ubiquitination-dependent activation of TANK-binding kinase 1.
Cell Rep, 3:747-758, 2013

PubMed 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.

PubMed: 23453972
DOI: 10.1016/j.celrep.2013.01.033

Experimental method

X-RAY DIFFRACTION (3.342 Å)