Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system

The crystal structures of human STING in the apo and c-di-GMP–bound states, supported by mutagenesis and biochemical data, reveal that c-di-GMP binds to preformed dimeric STING. c-di-GMP prolongs STING phosphorylation in vitro, which may contribute to downstream IFN signaling. These findings aid in understanding the innate immune response to bacterial infection. STING (stimulator of interferon genes) is an innate immune sensor of cyclic dinucleotides that regulates the induction of type I interferons. STING's C-terminal domain forms a V-shaped dimer and binds a cyclic diguanylate monophosphate (c-di-GMP) at the dimer interface by both direct and solvent-mediated hydrogen bonds. Guanines of c-di-GMP stack against the phenolic rings of a conserved tyrosine, and mutations at the c-di-GMP binding surface reduce nucleotide binding and affect signaling.