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

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

doi:10.1073/pnas.1507317112

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

Journal Article · Mon Jul 06 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1507317112· OSTI ID:1213725

Shi, Heping ^[1];

^[2]; Chen, Zhijian J. ^[3]; Chen, Chuo ^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biochemistry
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology. Howard Hughes Medical Inst.

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. In this paper, 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. Finally, our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein–ligand interactions.

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Research Organization:: Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States); Welch Foundation (United States)

Grant/Contract Number:: AC02-06CH11357; R01-GM-079554; R01-AI-093967; I-1868

OSTI ID:: 1213725

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 29; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 49 works

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Computational and NMR spectroscopy insights into the conformation of cyclic di-nucleotides Wang, Baifan; Wang, Zhenghua; Javornik, Uroš Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-16794-4	journal	November 2017
Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP Shang, Guijun; Zhang, Conggang; Chen, Zhijian J. Nature, Vol. 567, Issue 7748 https://doi.org/10.1038/s41586-019-0998-5	journal	March 2019
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59 BASIC BIOLOGICAL SCIENCES
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ligand conformation

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

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