The Human Type I Interferon Receptor: NMR Structure Reveals the Molecular Basis of Ligand Binding

The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution,...

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Veröffentlicht in:Structure (London) 2003-07, Vol.11 (7), p.791-802
Hauptverfasser: Chill, Jordan H, Quadt, Sabine R, Levy, Rina, Schreiber, Gideon, Anglister, Jacob
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Sprache:eng
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Zusammenfassung:The potent antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by a single receptor comprising two subunits, IFNAR1 and IFNAR2. The structure of the IFNAR2 IFN binding ectodomain (IFNAR2-EC), the first helical cytokine receptor structure determined in solution, reveals the molecular basis for IFN binding. The atypical perpendicular orientation of its two fibronectin domains explains the lack of C domain involvement in ligand binding. A model of the IFNAR2-EC/IFNα2 complex based on double mutant cycle-derived constraints uncovers an extensive and predominantly aliphatic hydrophobic patch on the receptor that interacts with a matching hydrophobic surface of IFNα2. An adjacent motif of alternating charged side chains guides the two proteins into a tight complex. The binding interface may account for crossreactivity and ligand specificity of the receptor. This molecular description of IFN binding should be invaluable for study and design of IFN-based biomedical agents.
ISSN:0969-2126
1878-4186
DOI:10.1016/S0969-2126(03)00120-5