Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING
- Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):8947-52. doi: 10.1073/pnas.1507317112.
- 1. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390;
- 2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
- 3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
- 4. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; [email protected].
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.