Structure of a DNA-bisdaunomycin complex.
Structure of a DNA-bisdaunomycin complex.
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DOI：
10.1021/bi9705218
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发表时间：
1997-05
期刊：
影响因子：
2.9
通讯作者：
G. G. Hu-G.;X. Shui;F. Leng;W. Priebe;J. Chaires;L. Williams
中科院分区：
文献类型：
--
作者：
G. G. Hu-G.;X. Shui;F. Leng;W. Priebe;J. Chaires;L. Williams
详细的结构数据库的应用现在已经在形成超紧密DNA复合物的新一代双蒽环类药物的成功设计中达到高潮[Chaires，J. B.，Leng，F.，Przewloka，T.，福克岛，Ling，Y. H、Perez-Soler，R.，& Priebe，W.（1997）J. Med. Chem. 40，261-266]。道诺霉素二聚体被设计成与DNA结合在复合物中，类似于在相邻位点插入的单体。本文所述工作的目标是用X射线晶体学确定这种新设计和合成的双蒽环类药物（WP 631）的有效成员是否按预期结合。WP 631由两个柔红霉素分子组成，通过二甲苯基将N3'连接到N3'。我们已经解决了2.2 A的X-射线晶体结构的WP 631绑定到[d（CGATCG）]2。我们证明，在详细的分子水平上，WP 631的设计策略是成功的。结合到[d（CGATCG）]2的WP 631和两个道诺霉素分子的结构提供了前所未有的机会，用于详细比较相同发色团的单插层和双插层复合物，使我们能够区分单插层和双插层的效果。差异主要集中在复合体的中心。DNA解旋和其他螺旋扭曲传播到WP 631复合物的中心比传播到柔红霉素复合物的中心更有效。
The application of detailed structural data bases has now culminated in the successful design of a new generation of bisanthracyclines that form ultratight DNA complexes [Chaires, J. B., Leng, F., Przewloka, T., Fokt, I., Ling, Y. H., Perez-Soler, R., & Priebe, W. (1997) J. Med. Chem. 40, 261-266]. Daunomycin dimers were designed to bind to DNA in complexes resembling those of monomers intercalated at adjacent sites. The goal of the work described here was to determine, with X-ray crystallography, if a potent member of this newly designed and synthesized class of bisanthracyclines (WP631) binds as intended. WP631 is composed of two daunomycin molecules, linked N3' to N3' by a xylyl group. We have solved the 2.2 A X-ray crystal structure of a complex of WP631 bound to [d(CGATCG)]2. We demonstrate, on a detailed molecular level, that the WP631 design strategy is a success. The structures of WP631 and two daunomycin molecules bound to [d(CGATCG)]2 provide the unprecedented opportunity for detailed comparison of mono- and bis-intercalated complexes of the same chromophore, allowing us to distinguish effects of mono-intercalation from those of bis-intercalation. Differences are focused primarily in the centers of the complexes. DNA unwinding and other helical distortions propagate more efficiently to the center of the WP631 complex than to the center of the daunomycin complex.