Distinct Dynamic and Conformational Features of Human STING in Response to 2′3′-cGAMP and c-di-GMP

Jingjing Guo, Jie Wang, Jingrong Fan, Yan Zhang, Wenpei Dong, Chang Po Chen

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


The human stimulator of interferon genes protein (hSTING) can bind cyclic dinucleotides (CDNs) to activate the production of type I interferons and inflammatory cytokines. These CDNs can be either bacterial secondary messengers, 3′3′-CDNs, or endogenous 2′3′-cGAMP. cGAMP, with a unique 2′–5′ bond, is the most potent activator of hSTING among all CDNs. However, current understanding of the molecular principles underlying the unique ability of 2′3′-cGAMP to potently activate hSTINGs other than 3′3′-CDNs remains incomplete. In this work, molecular dynamics simulations were used to provide an atomistic picture of the binding of 2′3′-cGAMP and one 3′3′-CDN (c-di-GMP) to hSTING. The results suggest that hSTING binds more strongly to 2′3′-cGAMP than to c-di-GMP, which prefers to bind with a more open and flexible state of hSTING. Finally, a potential “dock–lock–anchor” mechanism is proposed for the activation of hSTING upon the binding of a potent ligand. It is believed that deep insights into understanding the binding of hSTING with 3′3′-CDNs and the endogenous 2′3′-cGAMP would help to establish the principles underlying powerful 2′3′-cGAMP signaling and the nature of hSTING activation, as well as related drug design.

Original languageEnglish
Pages (from-to)1838-1847
Number of pages10
Issue number14
Publication statusPublished - 15 Jul 2019
Externally publishedYes


  • cyclic dinucleotides
  • cytokines
  • ligand effects
  • molecular dynamics
  • proteins


Dive into the research topics of 'Distinct Dynamic and Conformational Features of Human STING in Response to 2′3′-cGAMP and c-di-GMP'. Together they form a unique fingerprint.

Cite this