The binding conformation of Taxol in β-tubulin:: A model based on electron crystallographic density
The binding conformation of Taxol in β-tubulin:: A model based on electron crystallographic density
复制标题
DOI：
10.1073/pnas.051309398
复制
发表时间：
2001-04-24
影响因子：
11.1
通讯作者：
Nogales, E
中科院分区：
文献类型：
--
作者：
Snyder, JP;Nettles, JH;Nogales, E
化疗药物紫杉醇已知在β -微管蛋白的特定位点内相互作用。虽然该位点的一般位置已被光亲和标记和电子晶体学确定。原始数据不足以对束缚构象作出绝对的确定。我们现在将晶体学密度与紫杉醇构象分析联系起来，发现唯一的解是t形紫杉醇结构。这种t形结构或蝴蝶结构在β -微管蛋白位点内进行了优化，并显示出与α -微管蛋白亚基中B9-B10环部分的功能相似性。该模型为大量紫杉醇结构-活性关系数据提供了结构合理化，包括结合亲和力、光亲和力标记和人类癌细胞中的获得性突变。
The chemotherapeutic drug Taxol is known to interact within a specific site on beta -tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography. the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the beta -tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the alpha -tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structure-activity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells.