6O8B

Crystal structure of STING CTD in complex with TBK1

Summary for 6O8B

• Entry DOI: 10.2210/pdb6o8b/pdb
• Descriptor: Stimulator of interferon genes protein, 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 (3 entities in total)
• Functional Keywords: adaptor, kinase, complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 205461.57

Authors

Li, P.,Zhao, B.,Du, F. (deposition date: 2019-03-09, release date: 2019-05-22, Last modification date: 2023-10-11)

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

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: 31118511
DOI: 10.1038/s41586-019-1228-x

Experimental method

X-RAY DIFFRACTION (3.4 Å)