title: Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin.
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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110-1093, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Smith
authors.forename: Joydeep
authors.initials: J
authors.lastname: Ghosh
authors.forename: Jennifer Stine
authors.initials: JS
authors.lastname: Elam
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Michael G
authors.initials: MG
authors.lastname: Caparon
authors.forename: Tom
authors.initials: T
authors.lastname: Ellenberger
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013297:Streptococcus pyogenes / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D009243:NAD; D009244:NAD+ Nucleosidase