mTOR激酶的结构,机制和调节
Haijuan Yang1, Derek G Rudge, Joseph D Koos
1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Nature
|May 3, 2013
概括
哺乳动物中的拉巴素 (mTOR) 激酶结构的标显示出一种内在活性构造. 其活动由受限制的活跃站点访问来调节,由FRB域和抑制螺旋控制.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 哺乳动物的目标拉巴胺素 (mTOR) 是细胞生长的关键调节剂,在癌症中经常失调.
- 了解mTOR的结构和调节对于开发向癌症疗法至关重要.
研究的目的:
- 为了阐明截断的mTOR-mLST8复合物的共同晶体结构.
- 研究mTOR激活和抑制的结构基础.
主要方法:
- 确定mTOR-mLST8复合体与ATP过渡状态模拟器和抑制剂的共同晶体结构.
- 在体外生化测试以研究基质获取和抑制机制.
主要成果:
- mTOR激酶表现出一种内在活跃的构造,具有沉的活跃位点.
- FKBP12-拉帕米辛结合 (FRB) 域充当守门员,调节基质的访问.
- 拉帕-FKBP12通过阻断基质招募和限制活动现场访问来抑制mTOR.
- 激活mTOR的突变会影响控制活动站点访问的结构框架.
结论:
- 通过对其活性部位的限制访问,mTOR的激酶活性受到严格调节.
- FRB域在基质识别和mTOR调节中起着至关重要的作用.
- 结构洞察力为了解mTOR抑制剂的强度和特异性提供了基础.
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