@article{f44d7d6d17424f8686fc36052aa8d8f9,
title = "Cyclic GMP-AMP containing mixed Phosphodiester linkages is an endogenous high-affinity ligand for STING",
abstract = "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.",
author = "Xu Zhang and Heping Shi and Jiaxi Wu and Xuewu Zhang and Lijun Sun and Chuo Chen and ZhijianJ Chen",
note = "Funding Information: Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center, at the Advanced Photon Source. Argonne is operated by University of Chicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. We thank Drs. Diana Tomchick, James Chen, and Chad Brautigam at the Structural Biology Core at UT Southwestern Medical Center for assistance in crystallography and ITC experiments. We also thank Fenghe Du and Xiang Chen for technical assistance. This work was supported by NIH grants to Z.J.C. (RO1-AI-093967) and C.C. (RO1-GM-079554). The structural and biophysical studies of STING/cGAMP complex were performed by X.Z. Chemical synthesis, NMR, HPLC, and CD spectroscopy of cGAMP isomers were carried out by H.S. under the supervision of C.C. Mass spectrometry of cGAMPs and functional assays of cGAMPs and STING mutants were performed by J.W. Enzymatic synthesis and purification of the cGAS product were performed by L.S. The crystal structure analyses were performed with the assistance of Xuewu Zhang. The manuscript was written by Z.J.C., Xu Zhang, and C.C., and all authors agree with the contents. ",
year = "2013",
month = jul,
day = "25",
doi = "10.1016/j.molcel.2013.05.022",
language = "English (US)",
volume = "51",
pages = "226--235",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}