迪西奥斯塔丁柔性桥梁在溶液和β-氨酸分类体结合部位中的 conformations
Ashutosh S Jogalekar1, Krishnan Damodaran, Frederik H Kriel
1Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
Journal of the American Chemical Society
|February 9, 2011
概括
滴定 (DCT) 是一种具有多样化的结构的灵活分子,挑战了以前的结构模型. 一个特定的形状 (Conf-2) 与微管结合一致,表明其活动的新模式.
科学领域:
- 化学生物学是化学生物学.
- 结构生物学是结构生物学.
- 分子建模分子建模
背景情况:
- 狄基托斯坦 (DCT) 是一种复杂的多基基化,具有强大的微管聚合活性.
- 之前的研究提出了基于NMR数据的DCT的溶液结构 (2a) 和结合模式 (Conf-1).
研究的目的:
- 用计算方法探索DCT在不同溶剂中的构造格局.
- 根据新数据,重新评估 DCT 拟议的配置和绑定模式.
主要方法:
- 进行了广泛的基于力场的构造性搜索.
- 从溶液NMR数据中整合了几何参数.
- 应用了分子对接方法 (Glide,Autodock,RosettaLigand) 来建模DCT/β-tubulin相互作用.
主要成果:
- 该研究揭示了多种多样的DCT形状,表明显著的分子灵活性.
- 排除了之前提出的占主导地位的形状 (2a).
- 确定了一种特定的形状 (Conf-2),与TR-NOESY的微管结合的NMR数据相匹配.
- 一个低能结合模型 (Pose-2/Conf-2) 的DCT与β-tubulin的成功预测.
结论:
- DCT表现出相当大的形状灵活性,需要对其解决方案结构进行修订理解.
- 已识别的Conf-2构造为DCT与微管的相互作用提供了一个可信的模型.
- 预测的DCT/β-tubulin复合结构支持DCT的新兴结构-活动关系数据.
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