一个纳米体稳定β(2) 上腺体受体的活性状态的结构
Søren G F Rasmussen1, Hee-Jung Choi, Juan Jose Fung
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
Nature
|January 14, 2011
概括
研究人员使用纳米体稳定了活性G蛋白合受体 (GPCR) 状态. 这使得获得了第一个激素结合活性β-2上腺素受体 (β(2) AR) 的晶体结构,揭示了关键的激活机制.
科学领域:
- 结构生物学是结构生物学.
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
背景情况:
- G蛋白结合受体 (GPCRs) 是关键的药物标,但它们的活性状态不稳定,难以结构性地研究.
- 现有的晶体结构主要代表不活跃的GPCR构造.
- 了解GPCR激活对于药物发现和开发至关重要.
研究的目的:
- 为了获得与激素结合的活性状态GPCR的高分辨率晶体结构.
- 阐明由连接体激活GPCR的基础分子机制.
- 为理解GPCR信号提供结构基础.
主要方法:
- 一个驼类抗体碎片 (纳米体) 的生成,向人类β-2上腺素受体 (β(2) AR).
- 与一个激动剂的β(2) AR-纳米体复合物的联合结晶.
- 进行X射线晶体学以确定活性受体-纳米体复合物的结构.
- 活性结构与先前确定的非活性β(2) AR结构的比较.
主要成果:
- 成功获得了与纳米体复合的人类β(2) AR的激素结合,活性状态晶体结构.
- 与不活跃状态进行比较,发现结合体结合口袋内微妙但显著的变化.
- 一个主要的构造变化涉及11 Å向外移动的细胞质末端的跨膜段6.
- 观察到5号和7号跨膜片段的重排,与活跃的Opsin. 的重排相似.
结论:
- 纳米体有效地稳定了β(2) AR的活性构造,使其能够进行结构确定.
- 观察到的结构变化为在激动剂结合时GPCR激活的分子事件提供了关键的见解.
- 这项研究提供了一个结构模板,用于理解整个GPCR超级家族的联结体诱导激活.
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