Microtubules consists of αβ-tubulin heterodimers and are highly attractive targets for anti-cancer drugs. A broad range of agents have been identified to bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Podophyllotoxin is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of podophyllotoxin family drugs have been hindered by the lack of high-resolution structural information of the tubulin-agent complex. We report the first high-resolution (2.8 Å) structure of a podophyllotoxin family agent (4'-demethylepipodophyllotoxin, DMEP) complexed with tubulin and revealed the detailed interactions between DMEP and tubulin. Comparison of this structure and other CBSIs explains previous results of the structure-activity-relationship (SAR) studies, and provides insights into the development of new podophyllotoxin derivatives targeting the colchicine site.

中文翻译：

---

与微管蛋白复合的4'-去甲基表鬼臼毒素的结构为药物设计提供了理论依据。

微管由αβ-微管蛋白异二聚体组成，是抗癌药物的极具吸引力的靶标。已经鉴定出广泛的与微管蛋白结合并干扰微管组装的试剂，包括秋水仙碱结合位点抑制剂（CBSI）。鬼臼毒素是一种抑制微管组装的CBSI。然而，长期以来，缺乏微管蛋白-试剂复合物的高分辨率结构信息阻碍了鬼臼毒素家族药物的设计和开发。我们报告了与微管蛋白复合的鬼臼毒素家族药剂（4'-去甲基表鬼臼毒素，DMEP）的第一个高分辨率（2.8Å）结构，并揭示了DMEP和微管蛋白之间的详细相互作用。