预激活的阿里斯p44的晶体结构
Yong Ju Kim1, Klaus Peter Hofmann, Oliver P Ernst
1Institut für Medizinische Physik und Biophysik (CC2), Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
Nature
|April 23, 2013
概括
对于G蛋白结合受体 (GPCR) 信号传递至关重要的阿雷斯激活,涉及C尾部位移. 这项研究揭示了预激活的阿雷斯结构,揭示了关键的形状变化和一种新的激活机制.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子药理学分子药理学
背景情况:
- 阿雷斯通过阻断G蛋白相互作用和调节G蛋白独立通路来调节G蛋白结合受体 (GPCR) 信号传递.
- 阿雷斯激活涉及其碳氧终端尾部 (C尾部) 被受体附着的酸盐所取代,使其能够与活性GPCRs结合.
- 虽然已知非活跃的逮捕因结构,但C尾部位移诱导激活的机制尚不清楚.
研究的目的:
- 通过确定预先激活的阿雷斯的晶体结构来阐明阿雷斯激活的结构机制.
- 调查C尾位移在释放关键受体结合环和促进阿雷-GPCR相互作用中的作用.
- 了解使阿雷斯能够结合活性GPCRs的结构变化.
主要方法:
- 牛类阿雷斯-1拼接变体p44的X射线晶体学 (3.0 Å分辨率),C尾切断,预激活的形式.
- 位点定向光光谱检测以验证形状变化及其在阿雷斯激活和受体结合中的作用.
- 预激活的p44和基底1状态之间的比较结构分析.
主要成果:
- 44的晶体结构显示出与基底逮捕因-1截然不同的构造,其特点是中央极核和间键的断裂.
- 观察到两个阿雷斯叶之间发生了显著的旋转 (~21°),以及关键受体结合环 (指环,139环和门环) 的重新排列.
- 这些形状变化被验证为关键的阿雷斯激活和受体结合,表明一个机制,C尾位移释放这些循环.
结论:
- 逮捕激活涉及C尾部位移,这释放了关键的中央环从受限到扩展的受体相互作用形状.
- 在阿斯特林叶之间增加的灵活性可使其更好地适应活性GPCR表面.
- 这些发现提供了一个准备用于受体结合的逮捕因的结构快照,并提供了对视觉系统中自然截断的逮捕因功能的洞察.
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