| Summary: | Summary: To evade immunity, many viruses express interferon antagonists that target STAT transcription factors as a major component of pathogenesis. Because of a lack of direct structural data, these interfaces are poorly understood. We report the structural analysis of full-length STAT1 binding to an interferon antagonist of a human pathogenic virus. The interface revealed by transferred cross-saturation NMR is complex, involving multiple regions in both the viral and cellular proteins. Molecular mapping analysis, combined with biophysical characterization and in vitro/in vivo functional assays, indicates that the interface is significant in disease caused by a pathogenic field-strain lyssavirus, with critical roles for contacts between the STAT1 coiled-coil/DNA-binding domains and specific regions within the viral protein. These data elucidate the potentially complex nature of IFN antagonist/STAT interactions, and the spatial relationship of protein interfaces that mediate immune evasion and replication, providing insight into how viruses can regulate these essential functions via single multifunctional proteins. : Hossain et al. explore the binding surface of the multifunctional P-protein of rabies virus for STAT1, a protein that is essential for establishing the antiviral response of infected cells. They identify a complex interface comprising several distinct sites and demonstrate that targeted modifications of these can significantly attenuate pathogenic virus. Keywords: immune evasion, innate immunity, interferon, interferon antagonist, lyssavirus, nuclear magnetic resonance, P protein, rabies, STAT1, virus
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