title: Structure and mechanism of IFN-gamma antagonism by an orthopoxvirus IFN-gamma-binding protein.
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.
authors.affiliation: Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Nuara
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Walter
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Logsdon
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Yoon
authors.forename: Brandi C
authors.initials: BC
authors.lastname: Jones
authors.forename: Jill M
authors.initials: JM
authors.lastname: Schriewer
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
authors.forename: Mark R
authors.initials: MR
authors.lastname: Walter
mesh_terms: D000818:Animals; D002846:Chromatography, Affinity; D006860:Hydrogen Bonding; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018155:Orthopoxvirus / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D014764:Viral Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D007371:Interferon-gamma