Structure of STING bound to c-di-GMP Reveals the Mechanism of Cyclic Dinucleotide Recognition by the Immune System

STING, stimulator of interferon genes, is an innate immune sensor of cyclic dinucleotides that regulates the induction of type I interferons. STING C-terminal domain forms a V-shaped dimer and binds a c-di-GMP molecule at the dimer interface through direct and solvent-mediated hydrogen bonds. The guanine bases of c-di-GMP stack against the phenolic rings of a conserved tyrosine residue. Mutations at the c-di-GMP binding surface reduce nucleotide binding and affect signaling. Nucleic acids from bacteria or viruses induce potent immune responses in infected cells1,2. Cyclic dinucleotides such as cyclic di-guanine monophosphate (c-di-GMP) and cyclic diadenosine monophosphate (c-di-AMP) are immune stimulators that regulate the induction of type I interferons (IFN-α and β)3–5. These special nucleotides are secondary messenger molecules that regulate bacterial motility, biofilm formation, and virulence gene expression6,7. STING, a protein localized on the endoplasmic reticulum membrane, is an innate immune sensor of cyclic dinucleotides8. STING also plays critical roles in the innate immune response towards microbial DNA and RNA9,10. Two putative DNA sensors, IFI1