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Title: 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.
Authors:
 [1] ; ORCiD logo [2] ;  [3] ;  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biochemistry
  2. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology
  3. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology. Howard Hughes Medical Inst.
Publication Date:
OSTI Identifier:
1213725
Grant/Contract Number:
AC02-06CH11357; R01-GM-079554; R01-AI-093967; I-1868
Type:
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
Publisher:
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
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; cGAMP; STING; phosphodiester linkage; ligand conformation