Gigant Benoît, Wang Chunguang, Ravelli Raimond B G, Roussi Fanny, Steinmetz Michel O, Curmi Patrick A, Sobel André, Knossow Marcel
Laboratoire d'Enzymologie et Biochimie Structurales, UPR 9063, Centre National de la Recherche Scientifique, Bâtiment 34, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
Nature. 2005 May 26;435(7041):519-22. doi: 10.1038/nature03566.
Vinblastine is one of several tubulin-targeting Vinca alkaloids that have been responsible for many chemotherapeutic successes since their introduction in the clinic as antitumour drugs. In contrast with the two other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. Here we report the X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD). Vinblastine introduces a wedge at the interface of two tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the alpha-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate.
长春碱是几种靶向微管蛋白的长春花生物碱之一，自作为抗肿瘤药物引入临床以来，已在许多化疗中取得成功。与其他两类小的微管蛋白结合分子（紫杉醇和秋水仙碱）不同，长春碱的结合位点很大程度上未知，其药物作用的分子机制仍然难以捉摸。在此，我们报道了长春碱与微管蛋白结合并与RB3蛋白类stathmin结构域（RB3-SLD）形成复合物的X射线结构。长春碱在两个微管蛋白分子的界面处引入一个楔子，从而干扰微管蛋白的组装。结合电子显微镜和生化数据，该结构解释了长春碱诱导微管蛋白以牺牲微管生长为代价自组装成螺旋聚集体的现象。它还表明，长春碱和RB3-SLD结合位点的氨基末端部分在α-微管蛋白表面共享一个疏水凹槽，该凹槽位于微管中的分子间接触处。这是一个有吸引力的药物靶点，可通过界面干扰来扰乱微管动力学，由于微管蛋白易于自组装，它似乎非常适合作为这样的靶点。
