期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 29, 页码 8947-8952出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1507317112
关键词
cGAMP; STING; phosphodiester linkage; ligand conformation
资金
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- National Institutes of Health [R01-GM-079554, R01-AI-093967]
- Welch Foundation [I-1868]
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.
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