4IWP

Crystal structure and mechanism of activation of TBK1

Summary for 4IWP

• Entry DOI: 10.2210/pdb4iwp/pdb
• Related: 4IW0 4IWO 4IWQ
• 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 (2 entities in total)
• Functional Keywords: kinase, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9UHD2
• Total number of polymer chains: 1
• Total formula weight: 76457.26

Authors

Panne, D.,Larabi, A. (deposition date: 2013-01-24, release date: 2013-03-13, Last modification date: 2024-02-28)

Primary citation

Larabi, A.,Devos, J.M.,Ng, S.L.,Nanao, M.H.,Round, A.,Maniatis, T.,Panne, D.
Crystal structure and mechanism of activation of TANK-binding kinase 1.
Cell Rep, 3:734-746, 2013

PubMed Abstract: Tank-binding kinase I (TBK1) plays a key role in the innate immune system by integrating signals from pattern-recognition receptors. Here, we report the X-ray crystal structures of inhibitor-bound inactive and active TBK1 determined to 2.6 Å and 4.0 Å resolution, respectively. The structures reveal a compact dimer made up of trimodular subunits containing an N-terminal kinase domain (KD), a ubiquitin-like domain (ULD), and an α-helical scaffold dimerization domain (SDD). Activation rearranges the KD into an active conformation while maintaining the overall dimer conformation. Low-resolution SAXS studies reveal that the missing C-terminal domain (CTD) extends away from the main body of the kinase dimer. Mutants that interfere with TBK1 dimerization show significantly reduced trans-autophosphorylation but retain the ability to bind adaptor proteins through the CTD. Our results provide detailed insights into the architecture of TBK1 and the molecular mechanism of activation.

PubMed: 23453971
DOI: 10.1016/j.celrep.2013.01.034

Experimental method

X-RAY DIFFRACTION (3.065 Å)