Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule.
Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule.
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Pironetin 与 α-微管蛋白的半胱氨酸 316 发生共价反应，使微管不稳定
DOI：
10.1038/ncomms12103
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发表时间：
2016-06-30
影响因子：
16.6
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Yang J;Wang Y;Wang T;Jiang J;Botting CH;Liu H;Chen Q;Yang J;Naismith JH;Zhu X;Chen L
改变微管组装和拆卸的正常动力学的分子包括许多临床使用的抗癌药物。到目前为止，所有这些治疗药物都以β-微管蛋白为靶点，结构生物学已经解释了它们的作用基础，并允许设计新药。然而，通过改变β-微管蛋白同种型的分布，癌细胞变得对治疗有抗性。与α-微管蛋白结合的化合物的特征不太清楚，也未开发。已知天然产物吡柔酮与α-微管蛋白结合，是微管聚合的有效抑制剂。以前的报道已经确定了吡罗酮与赖氨酸-352残基反应，但是在此模型上设计的类似物的效力要低得多，这很难解释，阻碍了进一步的开发。我们报告的晶体学和质谱数据显示，pironetin通过Michael加成反应与α-微管蛋白中的半胱氨酸-316形成共价键。这些数据为合理设计以α-微管蛋白为靶点的化疗药物提供了依据。 微管组装和拆卸是许多抗癌治疗的靶点，其中β-微管蛋白是最常见的靶点。在这里，作者使用生物化学和生物物理技术证明pironetin与α-微管蛋白结合，从而抑制微管聚合，为合理设计新型抗癌药物提供了基础。
Molecules that alter the normal dynamics of microtubule assembly and disassembly include many anticancer drugs in clinical use. So far all such therapeutics target β-tubulin, and structural biology has explained the basis of their action and permitted design of new drugs. However, by shifting the profile of β-tubulin isoforms, cancer cells become resistant to treatment. Compounds that bind to α-tubulin are less well characterized and unexploited. The natural product pironetin is known to bind to α-tubulin and is a potent inhibitor of microtubule polymerization. Previous reports had identified that pironetin reacts with lysine-352 residue however analogues designed on this model had much lower potency, which was difficult to explain, hindering further development. We report crystallographic and mass spectrometric data that reveal that pironetin forms a covalent bond to cysteine-316 in α-tubulin via a Michael addition reaction. These data provide a basis for the rational design of α-tubulin targeting chemotherapeutics. Microtubule assembly and disassembly is the target of many anticancer therapies, with β-tubulin the most-frequent target. Here, the authors used biochemical and biophysical techniques to demonstrate pironetin binds to α-tubulin and thereby inhibits microtubule polymerization providing a basis for the rational design of novel anticancer drugs.