title: Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Heping
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jiaxi
authors.identifier: http://orcid.org/0000-0002-6976-4784
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; Chuo.Chen@utsouthwestern.edu.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007113:Immunity, Innate; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009712:Nucleotides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D000099197:STING Protein
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: STING; cGAMP; ligand conformation; phosphodiester linkage