期刊
EBIOMEDICINE
卷 9, 期 -, 页码 87-96出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.05.039
关键词
STING C-terminal tail; Molecular dynamics simulation; Type I IFNs; TBK1; cGAMP
资金
- Japan Society for the Promotion of Science [25430186, 25293079]
- Japan Agency for Medical Research and Development
- MEXT SPIRE Supercomputational Life Science
- Grants-in-Aid for Scientific Research [25430186] Funding Source: KAKEN
The innate immune protein Stimulator of interferon genes (STING) promotes the induction of interferon beta (IFN-Chi) 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-beta promoter, leading us to propose a new mechanism of STING activation. (C) 2016 The Authors. Published by Elsevier B.V.
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