结晶结构的TLR4-MD-2复合体与结合的内毒素抗剂Eritoran
Ho Min Kim1, Beom Seok Park, Jung-In Kim
1Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701.
Cell
|September 7, 2007
概括
收费类受体4 (TLR4) 和MD-2形成了一个复合体,可以检测细菌脂聚糖 (LPS). 埃里托兰是一种LPS模拟物,阻断了这种相互作用,提供了潜在的治疗益处.
科学领域:
- 结构生物学是结构生物学.
- 免疫学 免疫学 免疫学
- 天生的免疫的分子机制.
背景情况:
- 收费类受体4 (TLR4) 和骨髓分化因子2 (MD-2) 构成一个重要的复合体,用于识别格兰阴性细菌中的脂多糖 (LPS).
- 这种识别是天生的免疫反应的一个关键事件,触发炎症途径.
- 埃里托兰是一种LPS模拟物,通过与TLR4-MD-2复合体结合而起抗作用,抑制LPS诱导的激活.
研究的目的:
- 阐明TLR4-MD-2复合体形成的结构基础及其与LPS和Eritoran的相互作用.
- 了解由Eritoran引起的TLR4激活和对抗的分子机制.
- 为LRR家族中TLR4的非典型结构提供见解.
主要方法:
- 确定小鼠TLR4-MD-2复合体全长ECTDOMAIN的晶体结构.
- 生产和结构分析的人类TLR4-hagfish VLR杂交物与MD-2和Eritoran复合.
- 利用MD-2和TLR4的结构数据和突变发生实验,提出一个二元化模型.
主要成果:
- 确定了小鼠TLR4-MD-2ectodomain复合物的结构.
- 人类TLR4-VLR混合体与MD-2和Eritoran的结构揭示了结合接口和构造细节.
- MD-2与TLR4的N终端和中心域的形表面结合,而Eritoran在MD-2中引入了一个疏水口袋.
结论:
- TLR4表现出一种非典型的LRR结构,具有独特的β片特性.
- 结合TLR4的MD-2涉及与其N端和中心域的特定相互作用.
- 提出了一种LPS诱导的TLR4-MD-2二分化模型,强调了水相互作用在Eritoran对抗性中的作用.
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