AUROMOMYCIN: STRUCTURAL STUDY OF ANTICANCER

抗肿瘤抗生素金霉素(Aur)通过引起 DNA中的链断裂。该药物由非蛋白质发色团组成， 它是一种细胞毒性成分，还有一种叫做大莫霉素的载脂蛋白 (MCR，MR=10,700)。与抗肿瘤无关的载脂蛋白 活性，作为载体，保护发色团不被降解 并对其释放进行调控。本项目旨在研究一种 结晶学方法研究AUR细胞毒活性的分子基础 对抗生素成分的研究。目标是 在高分辨率下测定该化合物的晶体结构 全抗生素AUR、载脂蛋白MCR和发色团及其相互作用 与其他具有抗肿瘤活性的蛋白质的比较。这些 结构将毫不含糊地决定： 生色团；生色团与蛋白质结合的性质； 参与这种结合的氨基酸；官能团 发色团用于与蛋白质和DNA结合，并用于 链断裂活动；涉及的构象差异 发色团与蛋白质的结合。释义 结构可能暗示了生色团释放的可能机制和 确定与细胞膜相互作用所涉及的残基。一次 生色团的结构已知，可以研究它与DNA的结合 通过研究与DNA模型的络合物，在结晶学上 化合物或通过使用图形表示法进行建模研究 力学和能量提炼。这些结果的组合 生化和化疗研究将得到更好的结果 了解抗肿瘤药物和辅助药物在肿瘤治疗中的作用 潜在抗癌药物及作为特效药的蛋白质研究进展 传输系统。 最重要的进展是对载脂蛋白的研究。MCR 已经结晶成六种不同的晶体形式。分子 取代研究已经被用来确定晶体结构 其中两种形式。这些结构的改进工作已经开始。8月 得到了与MCR晶体同构的晶体。

The antitumor antibiotic auromomycin (AUR) inhibits cell growth by causing strand breaks in DNA. The drug is composed of a non-protein chromophore, which is the cytotoxic component, and an apoprotein called macromomycin (MCR, Mr=10,700). The apoprotein, which is not involved in the antitumor activity, serves as a carrier, protecting the chromophore from degradation and regulating its release. This project is designed to study on a molecular basis the cytotoxic activity of AUR by means of crystallographic studies of the components of the antibiotic. The objectives are the determination at high resolution of the crystal structures of the holoantibiotic AUR, the apoprotein MCR and the chromophore and their comparisons with those of other proteins with antitumor activity. These structures will determine unambiguously: the chemical composition of the chromophore; the nature of the binding of the chromophore to the protein; the amino acids involved in this binding; the functional groups the chromophore employs for binding to the protein and to the DNA and for the strand scission activity; the conformational differences involved in the binding of the chromophore by the protein. Interpretation of the structures may suggest possible mechanisms for the chromophore release and identify residues involved in the interaction with the cell membrane. Once the structure of the chromophore is known its binding to DNA can be studied either crystallographically by the study of complexes with DNA model compounds or by modelling studies using graphic representations, moelcular mechanics and energy refinement. Combination of the results of these studies with biochemical and chemotherapeutic studies will result better understanding of the actions of the antitumor agent and aid in the development of potential anticancer drugs and proteins as specific drug delivery systems. The most important progress has been in the study of the apoprotein. MCR has been crystallized in six different crystal forms. Molecular replacement studies have been used to determine the crystal structures of two of these forms. Refinement of these structures has been started. AUR crystals have been obtained which are isomorphous with those of MCR.