Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein

• Published in: Journal of chemical information and modeling 2023-12, Vol.63 (23), p.7373-7381
• Main Authors: Li, Rui, Chen, Lin, He, Xinheng, Cao, Duanhua, Zhang, Zehong, Jiang, Hualiang, Chen, Kaixian, Cheng, Xi
• Format: Article
• Language: English
• Subjects: Binding; Computational Chemistry; Free energy; Genes; Helices; Interferon; Kinases; Molecular dynamics; Simulation; Stimulators
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.3c00984

The stimulator of interferon genes (STING) is an important therapeutic target for cancer diseases. The activated STING recruits downstream tank-binding kinase 1 (TBK1) to trigger several important immune responses. However, the molecular mechanism of how agonist molecules mediate the STING–TBK1 interactions remains elusive. Here, we performed molecular dynamics simulations to capture the conformational changes of STING and TBK1 upon agonist binding. Our simulations revealed that multiple helices (α5–α7) and especially three loops (loop 6, loop 8, and C-terminal tail) of STING participated in the allosteric mediation of the STING–TBK1 interactions. Consistent results were also observed in the simulations of the constitutive activating mutant of STING (R284S). We further identified α5 as a key region in this agonist-induced activation mechanism of STING. Free-energy perturbation calculations of multiple STING agonists demonstrated that an alkynyl group targeting α5 is a determinant for agonist activities. These results not only offer deeper insights into the agonist-induced allosteric mediation of STING–TKB1 interactions but also provide a guidance for future drug development of this important therapeutic target.