Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING

Heping Shi, Jiaxi Wu, Zhijian J. Chen, Chuo Chen

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21 Scopus citations


Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2′3′-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2′3′-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2′3′-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions.

Original languageEnglish (US)
Pages (from-to)8947-8952
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
Publication statusPublished - Jul 21 2015



  • cGAMP
  • Ligand conformation
  • Phosphodiester linkage

ASJC Scopus subject areas

  • General

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