c-Src和c-Abl激酶的不同灵活性调节了可药性无活性构造的可访问性
Silvia Lovera1, Ludovico Sutto, Ralitza Boubeva
1Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, E-28029 Madrid, Spain.
Journal of the American Chemical Society
|January 28, 2012
概括
抗癌药物伊马替尼向蛋白激酶c-Src和c-Abl. 激酶灵活性的差异解释了伊马替尼布的存在.
科学领域:
- 生物化学和分子生物学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- c-Src和c-Abl是密切相关的蛋白激酶和重要的抗癌标.
- 这些激酶对抗癌药物伊马替尼 (imatinib) 具有不同的敏感性.
- 伊马替尼选择性地结合到一个非活性激酶构成 (DFG-out).
研究的目的:
- 研究c-Src和c-Abl.中的DFG形状转变.
- 阐明 imatinib 在 c-Src 和 c-Abl 之间具有差异性选择性的分子基础.
主要方法:
- 广泛的分子动力学模拟.
- 免费能源计算.
- 异热定位热量计. 异热定位热量计.
主要成果:
- 在c-Src和c-Abl中对DFG-in到DFG-out转换的重建的自由能量表面.
- 在c-Src和c-Abl.之间确定了不同的灵活性配置文件.
- 证明了每个激酶的DFG-out形态的不同稳定性.
结论:
- c-Src和c-Abl的差异灵活性影响了DFG-out的形状稳定性.
- 激酶灵活性是伊马丁尼布选择性的关键决定因素.
- 了解这些动态可以为更有选择性的激酶抑制剂的设计提供信息.
相关概念视频
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