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, 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.
Chill
Jordan H
JH
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Quadt
Sabine R
SR
Levy
Rina
R
Schreiber
Gideon
G
Anglister
Jacob
J
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
D007370:Interferon Type I; D008024:Ligands; D017471:Receptors, Interferon