6O8C
Crystal structure of STING CTT in complex with TBK1
Summary for 6O8C
| Entry DOI | 10.2210/pdb6o8c/pdb |
| Descriptor | Serine/threonine-protein kinase TBK1, Stimulator of interferon genes protein, N-(3-{[5-iodo-4-({3-[(thiophen-2-ylcarbonyl)amino]propyl}amino)pyrimidin-2-yl]amino}phenyl)pyrrolidine-1-carboxamide (3 entities in total) |
| Functional Keywords | adaptor, kinase, complex, immune system |
| Biological source | Mus musculus (Mouse) More |
| Total number of polymer chains | 4 |
| Total formula weight | 162328.60 |
| Authors | |
| Primary citation | Zhao, B.,Du, F.,Xu, P.,Shu, C.,Sankaran, B.,Bell, S.L.,Liu, M.,Lei, Y.,Gao, X.,Fu, X.,Zhu, F.,Liu, Y.,Laganowsky, A.,Zheng, X.,Ji, J.Y.,West, A.P.,Watson, R.O.,Li, P. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature, 569:718-722, 2019 Cited by PubMed Abstract: Nucleic acids from bacteria or viruses induce potent immune responses in infected cells. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor. It catalyses the synthesis of cyclic GMP-AMP (cGAMP), which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK1. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons. However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFNβ after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders. PubMed: 31118511DOI: 10.1038/s41586-019-1228-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.17 Å) |
Structure validation
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