Ligand-induced Ordering of the C-terminal Tail Primes STING for Phosphorylation by TBK1

EBioMedicine

Ken J. Ishii¹  Fumihiko Takeshita¹  Nao Jounai¹  Kenji Mizuguchi²  Yuko Tsuchiya² 

[1]Laboratory of Aduvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan

[2]Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan

关键词: STING C-terminal tail;    Molecular dynamics simulation;    Type I IFNs;    TBK1;    cGAMP.;   

DOI  :  10.1016/j.ebiom.2016.05.039

来源: DOAJ

【 摘 要 】

The innate immune protein Stimulator of interferon genes (STING) promotes the induction of interferon beta (IFN-β) production via the phosphorylation of its C-terminal tail (CTT) by TANK-binding kinase 1 (TBK1). Potent ligands of STING are, therefore, promising candidates for novel anti-cancer drugs or vaccine adjuvants. However, the intrinsically flexible CTT poses serious problems in in silico drug discovery. Here, we performed molecular dynamics simulations of the STING fragment containing the CTT in ligand-bound and unbound forms and observed that the binding of a potent ligand cyclic GMP-AMP (cGAMP) induced a local structure in the CTT, reminiscent of the known structure of a TBK1 substrate. The subsequent molecular biological experiments confirmed the observed dynamics of the CTT and identified essential residues for the activation of the IFN-β promoter, leading us to propose a new mechanism of STING activation.

【 授权许可】

Unknown