The bound conformation of microtubule-stabilizing agents:: NMR insights into the bioactive 3D structure of discodermolide and dictyostatin
The bound conformation of microtubule-stabilizing agents:: NMR insights into the bioactive 3D structure of discodermolide and dictyostatin
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DOI：
10.1002/chem.200800039
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发表时间：
2008-01-01
影响因子：
4.3
通讯作者：
Jimenez-Barbero, Jesus
中科院分区：
文献类型：
--
作者：
Canales, Angeles;Matesanz, Ruth;Jimenez-Barbero, Jesus
基于NMR实验数据与分子力学计算和对接程序相结合的协议已被用来确定两个微管稳定的微管结合构象。药物，discodermolide（DDM）和dictyostatin（DCT）。这些数据表明，微管蛋白在组装的微管识别DDM通过构象选择过程，在水溶液中的主要构象之间的分子骨架的微小变化，并结合组装的微管。对于DCT，推导出的绑定几何提出了一些关键的构象差异，围绕某些扭转角，相对于解决方案中的主要构象，仍然显示流动性，即使绑定。DCT的结合构象类似于DDM，并提供与受体非常相似的接触。竞争实验表明，这两种分子都与紫杉烷结合位点竞争。提出了DDM和DCT与微管蛋白结合方式的模型。
A protocol based on a combination of NMR experimental data with molecular mechanics calculations and docking procedures has been employed to determine the microtubule-bound conformation of two microtubule-stabilizing. agents, discodermolide (DDM) and dictyostatin (DCT). The data indicate that tubulin in assembled microtubules recognizes DDM through a conformational selection process, with minor changes in the molecular skeleton between the major conformer in water solution and that bound to assembled microtubules. For DCT, the deduced bound geometry presents some key conformation differences around certain torsion angles, with respect to the major conformer in solution, and still displays mobility even when bound. The bound conformer of DCT resembles that of DDM and provides very similar contacts with the receptor. Competition experiments indicate that both molecules compete with the taxane-binding site. A model of the binding mode of DDM and DCT to tubulin is proposed.