Activation of STING Based on Its Structural Features

Abstract

The cGAS-cGAMP-STING pathway is an important innate immune signaling cascade responsible for the sensing of abnormal cytosolic double-stranded DNA (dsDNA), which is a hallmark of infection or cancers. Recently, tremendous progress has been made in the understanding of the STING activation mechanism from various aspects. In this review, the molecular mechanism of activation of STING protein based on its structural features is briefly discussed. The underlying molecular mechanism of STING activation will enable us to develop novel therapeutics to treat STING-associated diseases and understand how STING has evolved to eliminate infection and maintain immune homeostasis in innate immunity.

Discovery of BI 7446: A Potent Cyclic Dinucleotide STING Agonist with Broad-Spectrum Variant Activity for the Treatment of Cancer

“…Intermediate 9.2 (6.90 g, 14.6 mmol) was dissolved in DCM (150 mL). At 0 °C, 2,6-lutidine (2.53 mL, 21.9 mmol) and tertbutyldimethylsilyl trifluoromethanesulfonate (5.02 mL, 21.9 mmol) were added, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM and washed three times with a saturated solution of NH 4 Cl. The organic layer was dried, filtered, and concentrated.…”

“…To this solution was added 4,4′-dimethoxytrityl chloride (3.66 g, 10.8 mmol) in portions, and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and a saturated solution of NaHCO 3 . The organic layer was washed with a saturated solution of NH 4 Cl and NaHCO 3 , dried, filtered, and evaporated under reduced pressure. The residue is triturated with propyl acetate.…”

Unlocking STING as a Therapeutic Antiviral Strategy

“…Starting from the ammino-terminal portion, STING presents four transmembrane domains (TMD) responsible for the localization in the organelles’ membrane, endoplasmic reticulum, and mitochondrion. The main domain, comprehending aa 139–379, is the cytosolic domain (CTD), located in the carboxyl-terminal region in which reside the ligand-binding domain (LBD) and the highly conserved dimerization motif GXXXS required for STING dimerization; the remaining domains are considered linker domains [ 50 ]. STING exerts its function through homodimerization by adopting the α+ β fold, involving five-stranded sheets in the center and four helices in the periphery [ 50 ] ( Figure 3 B).…”

“…The main domain, comprehending aa 139–379, is the cytosolic domain (CTD), located in the carboxyl-terminal region in which reside the ligand-binding domain (LBD) and the highly conserved dimerization motif GXXXS required for STING dimerization; the remaining domains are considered linker domains [ 50 ]. STING exerts its function through homodimerization by adopting the α+ β fold, involving five-stranded sheets in the center and four helices in the periphery [ 50 ] ( Figure 3 B). The dimerization motif localized in the transmembrane region identified as LBDα1 is essential for STING activity, as demonstrated through mutagenesis studies [ 51 ].…”

“…pTBK1 attracts interferon regulatory factor 3 (IRF3), forming the STING–TBK1–IRF3 complex. Although the complex formation dynamics are still unclear, the interaction leads to IRF3 dimerization and phosphorylation mediated by pTBK1 [ 50 ]. Then, the active IRF3 dimer translocates in the nucleus, where it binds the IFN-I promoter, leading to IFN-I production [ 36 , 61 , 62 ].…”