The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding

被引:71
作者
Chill, JH
Quadt, SR
Levy, R
Schreiber, G
Anglister, J [1 ]
机构
[1] Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel
基金
美国国家卫生研究院;
关键词
D O I
10.1016/S0969-2126(03)00120-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 ecto-domain (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.
引用
收藏
页码:791 / 802
页数:12
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