Structural Basis of Streptococcus pyogenes Immunity to Its NAD+ Glycohydrolase Toxin

SummaryThe virulence of Gram-positive bacteria is enhanced by toxins like the Streptococcus pyogenes β-NAD+ glycohydrolase known as SPN. SPN-producing strains of S. pyogenes additionally express the protein immunity factor for SPN (IFS), which forms an inhibitory complex with SPN. We have determined crystal structures of the SPN-IFS complex and IFS alone, revealing that SPN is structurally related to ADP-ribosyl transferases but lacks the canonical binding site for protein substrates. SPN is instead a highly efficient glycohydrolase with the potential to deplete cellular levels of β-NAD+. The protective effect of IFS involves an extensive interaction with the SPN active site that blocks access to β-NAD+. The conformation of IFS changes upon binding to SPN, with repacking of an extended C-terminal α helix into a compact shape. IFS is an attractive target for the development of novel bacteriocidal compounds functioning by blocking the bacterium's self-immunity to the SPN toxin.

► SPN is structurally homolgous to ADP-ribosyl transferase
► IFS interacts extensively with SPN, blocking access to the SPN active site
► IFS adopts different conformations in solution and when bound to SPN