Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin

Structure. 2011 Feb 9;19(2):192-202. doi: 10.1016/j.str.2010.12.013.

Abstract

The 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • Bacterial Toxins / metabolism*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Models, Molecular
  • Molecular Sequence Data
  • NAD / metabolism
  • NAD+ Nucleosidase / genetics
  • NAD+ Nucleosidase / immunology
  • NAD+ Nucleosidase / metabolism*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Streptococcus pyogenes / immunology
  • Streptococcus pyogenes / metabolism
  • Streptococcus pyogenes / pathogenicity
  • Virulence

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • NAD
  • NAD+ Nucleosidase

Associated data

  • PDB/3PNT
  • PDB/3QB2