title: The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding.
abstract: 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/IFNalpha2 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 IFNalpha2. 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.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Jordan H
authors.initials: JH
authors.lastname: Chill
authors.forename: Sabine R
authors.initials: SR
authors.lastname: Quadt
authors.forename: Rina
authors.initials: R
authors.lastname: Levy
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
authors.forename: Jacob
authors.initials: J
authors.lastname: Anglister
mesh_terms: D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017471:Receptors, Interferon / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D007370:Interferon Type I; D008024:Ligands; D017471:Receptors, Interferon