一个激素的蛋白质激素的功能模仿:EPO受体复合体在2.8 A处
O Livnah1, E A Stura, D L Johnson
1Department of Molecular Biology and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|July 26, 1996
概括
一个小通过诱导受体二分化,模仿了血液生成的生长激素 - - 红色素 (EPO). 这一发现表明了非性小分子模仿剂对EPO和其他细胞因子的潜在设计.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子内分泌学分子内分泌学
背景情况:
- 用小分子模仿蛋白质功能是一项挑战.
- 红色素 (EPO) 是一种造血生长激素,对红细胞的产生至关重要.
- 埃博通过与其相似的第1类细胞因子受体结合来发挥其生物活性.
研究的目的:
- 通过一个与人无关的小分子研究红色素 (EPO) 功能模仿的结构基础.
- 阐明一种激活剂诱导EPO受体二元化和信号转导的机制.
- 探索设计EPO和其他细胞因子的新型小分子模仿剂的潜力.
主要方法:
- 使用X射线晶体学来确定EPO受体细胞外域的结构,该结构与2.8A分辨率的20残留周期性激素复合.
- 结构分析侧重于由联体诱导的受体二分化模式.
- 观察到的二元组合与人类生长激素 (hGH) 受体复合物的比较.
主要成果:
- 一个有20个残留的循环,其序列与EPO无关,功能上模仿了造血生长激素.
- 晶体结构显示,二聚体会诱导EPO受体的近乎完美的双倍二聚化.
- 观察到的受体二元组合与hGH诱导的不同,这表明了信号转导的替代模式.
- 定义的EPO受体结合部位对应于hGH受体的功能性表位体.
结论:
- 一个最小的配体可以有效地模仿像EPO这样的大型蛋白质激素的生物活性.
- 类诱导的受体二分化是启动信号转导的关键机制.
- 这些发现支持设计EPO和其他细胞因子受体的非性小分子模仿剂的可行性.
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