Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING

Xu Zhang, Heping Shi, Jiaxi Wu, Xuewu Zhang, Lijun Sun, Chuo Chen, ZhijianJ Chen

Research output: Contribution to journalArticle

325 Scopus citations


The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMPrevealed the structural basis of this high-affinitybinding and a ligand-induced conformational change in STING that may underlie its activation.

Original languageEnglish (US)
Pages (from-to)226-235
Number of pages10
JournalMolecular Cell
Issue number2
Publication statusPublished - Jul 25 2013


ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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