Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING
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.
- 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.
- Publication Date:
- OSTI Identifier:
- Grant/Contract Number:
- AC02-06CH11357; R01-GM-079554; R01-AI-093967; I-1868
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 112; Journal Issue: 29; Journal ID: ISSN 0027-8424
- National Academy of Sciences, Washington, DC (United States)
- Research Org:
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
- Sponsoring Org:
- USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States); Welch Foundation (United States)
- Country of Publication:
- United States
- 59 BASIC BIOLOGICAL SCIENCES; cGAMP; STING; phosphodiester linkage; ligand conformation
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