2' 2' -cGAMP (sodium salt)

2′2′-Cyclic GMP-AMP sodium salt (2′2′-cGAMP, CAS: 1465774-27-9) is a synthetic symmetric cyclic dinucleotide. It couples one guanylate and one adenylate through two 2′5′ phosphodiester bonds in a head-to-tail cyclization. The two 2′5′ bonds give it a geometry distinct from 2′3′-cGAMP.

2′2′-cGAMP binds the STING ligand-binding domain, driving STING dimerization and translocation to the Golgi, where STING recruits and activates TBK1; TBK1 phosphorylates IRF3 and IKKβ to launch type I interferon and NF-κB pathways. 2′2′-cGAMP binds STING with lower affinity than 2′3′-cGAMP yet induces comparable interferon levels across a similarly low concentration range - this dissociation between weak binding and strong activation shows that STING activation depends on the phosphodiester geometry, not merely on binding strength.

Researchers run 2′2′-cGAMP and 2′3′-cGAMP side by side, comparing the concentrations required to activate STING and the interferon levels each induces, to examine how the STING ligand-binding domain discriminates between different phosphodiester geometries. 2′2′-cGAMP therefore serves as a control molecule in mechanistic studies of the STING pathway.

References:

Gao P, Ascano M, Zillinger T, et al. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell. 2013;154(4):748-762.

Zhang X, Shi H, Wu J, et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell. 2013;51(2):226-235.