4EUT

Structure of BX-795 Complexed with Unphosphorylated Human TBK1 Kinase-ULD Domain

Summary for 4EUT

• Entry DOI: 10.2210/pdb4eut/pdb
• Related: 4EUU
• 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, IODIDE ION, ... (5 entities in total)
• Functional Keywords: kinase, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q9UHD2
• Total number of polymer chains: 2
• Total formula weight: 91959.69

Authors

Ma, X.,Helgason, E.,Phung, Q.T.,Quan, C.L.,Iyer, R.S.,Lee, M.W.,Bowman, K.K.,Starovasnik, M.A.,Dueber, E.C. (deposition date: 2012-04-25, release date: 2012-05-23, Last modification date: 2024-02-28)

Primary citation

Ma, X.,Helgason, E.,Phung, Q.T.,Quan, C.L.,Iyer, R.S.,Lee, M.W.,Bowman, K.K.,Starovasnik, M.A.,Dueber, E.C.
Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation.
Proc.Natl.Acad.Sci.USA, 109:9378-9383, 2012

PubMed Abstract: Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.

PubMed: 22619329
DOI: 10.1073/pnas.1121552109

Experimental method

X-RAY DIFFRACTION (2.6 Å)