Modulation of Microtubule Interprotofilament Interactions by Modified Taxanes
Modulation of Microtubule Interprotofilament Interactions by Modified Taxanes
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修饰紫杉烷对微管原丝间相互作用的调节
DOI：
10.1016/j.bpj.2011.11.005
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发表时间：
2011-12-21
影响因子：
3.4
通讯作者：
Fernando Diaz, Jose
中科院分区：
文献类型：
--
作者：
Matesanz, Ruth;Rodriguez-Salarichs, Javier;Fernando Diaz, Jose
与紫杉醇和多西他赛组装的微管在其原丝数量上不同，反映了微管壁中α β-微管蛋白分子之间的侧向缔合的修饰。微管结构的这些修改，通过尚未表征的机制，最有可能与微管蛋白-微管蛋白相互作用的变化负责微管稳定这些抗肿瘤化合物。我们已经使用了一套修改的紫杉烷研究这些配体的微管稳定的结构机制。使用小角X-射线散射，我们已经确定如何修改的形状和大小的紫杉烷取代基的interprotofilament角度和它们的数量的变化的结果。所观察到的效果已被解释使用NMR辅助对接和紫杉烷结合在微管孔和管腔网站的分子动力学模拟。建模结果表明，紫杉烷核心的C7和C10位置的取代基的大小的修改影响微管横向相互作用（M-环，S3 β链，和H3螺旋），调节相邻原丝之间的接触的三个关键要素的构象。此外，C2位取代基的修饰会使结合位点中的配体略微重排，从而修饰C7取代基与M环的相互作用。
Microtubules assembled with paclitaxel and docetaxel differ in their numbers of protofilaments, reflecting modification of the lateral association between alpha beta-tubulin molecules in the microtubule wall. These modifications of microtubule structure, through a not-yet-characterized mechanism, are most likely related to the changes in tubulin-tubulin interactions responsible for microtubule stabilization by these antitumor compounds. We have used a set of modified taxanes to study the structural mechanism of microtubule stabilization by these ligands. Using small-angle x-ray scattering, we have determined how modifications in the shape and size of the taxane substituents result in changes in the interprotofilament angles and in their number. The observed effects have been explained using NMR-aided docking and molecular dynamic simulations of taxane binding at the microtubule pore and luminal sites. Modeling results indicate that modification of the size of substituents at positions C7 and C10 of the taxane core influence the conformation of three key elements in microtubule lateral interactions (the M-loop, the S3 beta-strand, and the H3 helix) that modulate the contacts between adjacent protofilaments. In addition, modifications of the substituents at position C2 slightly rearrange the ligand in the binding site, modifying the interaction of the C7 substituent with the M-Ioop.