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

Craig L. Smith, Joydeep Ghosh, Jennifer Stine Elam, Jerome S. Pinkner, Scott J. Hultgren, Michael G. Caparon, Tom Ellenberger

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)192-202
Number of pages11
JournalStructure
Volume19
Issue number2
DOIs
StatePublished - Feb 9 2011

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