Structure, binding, and antagonists in the IL-4/IL-13 receptor system

被引:144
作者
Mueller, TD
Zhang, JL
Sebald, W
Duschl, A
机构
[1] Salzburg Univ, Inst Chem & Biochem, A-5020 Salzburg, Austria
[2] Univ Wurzburg, Bioctr, D-97074 Wurzburg, Germany
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2002年 / 1592卷 / 03期
关键词
IL-4; IL-13; allergy; antagonist; protein structure;
D O I
10.1016/S0167-4889(02)00318-X
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
Interleukin-4 (IL-4) and IL-13 are the only cytokines known to bind to the receptor chain IL-4Ralpha. Receptor sharing by these two cytokines is the molecular basis for their overlapping biological functions. Both are key factors in the development of allergic hypersensitivity, and they also play a major role in exacerbating allergic and asthmatic symptoms. Knowledge of structure and function of this system has allowed the development of inhibitors that block the interaction between the cytokines and their shared receptor. Mutational analysis of IL-4 has revealed variants with high-affinity binding to IL-4Ralpha but no detectable affinity for the second receptor subunit, which is either gammac or IL-13Ralpha1. These IL-4 antagonists fail to induce signal transduction and block IL-4 and IL-13 effects in vitro. IL-4 antagonists prevent the development of allergic disease in vivo and an antagonistic variant of human IL-4 is now in clinical trials for asthma. Detailed knowledge of the site of interaction of IL-4 and IL-4Ralpha has been gained by structure analysis of the complex of these two proteins and through functional studies employing mutants of IL-4 and its receptor subunits. Based on these new data, the hitherto elusive goal of designing small molecular mimetics may be feasible. (C) 2002 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:237 / 250
页数:14
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