在无体状态下,Frizzled 4受体的晶体结构
Shifan Yang1, Yiran Wu1, Ting-Hai Xu2
1iHuman Institute, ShanghaiTech University, Shanghai, China.
Nature
|August 24, 2018
概括
对于Wnt信号传递至关重要的Frizzled受体 (FZD) 具有独特的结构,阻碍了传统的连接体结合. 这一发现可能解释了开发针对FZD的药物和探测器所面临的挑战.
科学领域:
- 结构生物学
- 生物化学
- 细胞信号传输
背景情况:
- 状受体 (FZD) 是F类G蛋白合受体 (GPCR),对于发育和成年生物的Wnt信号提供至关重要.
- 在Wnt信号传递中,FZD作为关键的调解者,使其成为药物开发和研究探测的重要目标.
研究的目的:
- 确定人类Frizzled 4受体 (FZD4) 跨膜域的原子分辨率结构.
- 调查FZD中的连接和激活机制的结构基础.
主要方法:
- 通过X射线结晶学获得FZD4跨膜域的原子分辨率结构.
- 微秒级的分子动力学模拟.
- 突变分析以确定关键的残留物和参与激活的结构元素.
主要成果:
- 揭示了FZD4异常的跨膜结构,与其他GPCR不同,具有短,密集的螺旋VI.
- 鉴定出一种狭窄的,不适合传统GPCR配体的水友结合口袋,并发现它在FZD中保持.
- 在螺旋VII中发现了两个合的动态扭曲,
结论:
- 独特的FZD4结构及其联结口袋对传统药物开发构成挑战.
- 在FZD中保留的狭窄口袋可能解释了开发特定连接体的困难.
- FZD可能使用与其他GPCR不同的一种新型联体识别和激活机制,涉及 VII动态.
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