Structure and mechanism of IFN-gamma antagonism by an orthopoxvirus IFN-gamma-binding protein

Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1861-6. doi: 10.1073/pnas.0705753105. Epub 2008 Feb 5.

Abstract

Ectromelia virus (ECTV) encodes an IFN-gamma-binding protein (IFN-gammaBP(ECTV)) that disrupts IFN-gamma signaling and its ability to induce an antiviral state within cells. IFN-gammaBP(ECTV) is an important virulence factor that is highly conserved (>90%) in all orthopoxviruses, including variola virus, the causative agent of smallpox. The 2.2-A crystal structure of the IFN-gammaBP(ECTV)/IFN-gamma complex reveals IFN-gammaBP(ECTV) consists of an IFN-gammaR1 ligand-binding domain and a 57-aa helix-turn-helix (HTH) motif that is structurally related to the transcription factor TFIIA. The HTH motif forms a tetramerization domain that results in an IFN-gammaBP(ECTV)/IFN-gamma complex containing four IFN-gammaBP(ECTV) chains and two IFN-gamma dimers. The structure, combined with biochemical and cell-based assays, demonstrates that IFN-gammaBP(ECTV) tetramers are required for efficient IFN-gamma antagonism.

Publication types

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

MeSH terms

  • Animals
  • Chromatography, Affinity
  • Hydrogen Bonding
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / metabolism
  • Mice
  • Orthopoxvirus / metabolism*
  • Protein Binding
  • Protein Conformation
  • Viral Proteins / chemistry
  • Viral Proteins / isolation & purification
  • Viral Proteins / metabolism*

Substances

  • Viral Proteins
  • Interferon-gamma

Associated data

  • PDB/3BES
  • PDB/RCSB045439