Coste F, Malinge J M, Serre L, Shepard W, Roth M, Leng M, Zelwer C
Centre de Biophysique Moléculaire, Centre de National de la Recherche Scientifique, affiliated to the Université d'Orléans, rue Charles Sadron, 45071 Orleans Cedex, France.
Nucleic Acids Res. 1999 Apr 15;27(8):1837-46. doi: 10.1093/nar/27.8.1837.
cis-diamminedichloroplatinum (II) (cisplatin) is a powerful anti-tumor drug whose target is cellular DNA. In the reaction between DNA and cisplatin, covalent intrastrand and interstrand cross-links (ICL) are formed. Two solution structures of the ICL have been published recently. In both models the double-helix is bent and unwound but with significantly different angle values. We solved the crystal structure at 100K of a double-stranded DNA decamer containing a single cisplatin ICL, using the anomalous scattering (MAD) of platinum as a unique source of phase information. We found 47 degrees for double-helix bending and 70 degrees for unwinding in agreement with previous electrophoretic assays. The crystals are stabilized by intermolecular contacts involving two cytosines extruded from the double-helix, one of which makes a triplet with a terminal G.C pair. The platinum coordination is nearly square and the platinum residue is embedded into a cage of nine water molecules linked to the cross-linked guanines, to the two amine groups, and to the phosphodiester backbone through other water molecules. This water molecule organization is discussed in relation with the chemical stability of the ICL.
顺二氯二氨合铂（II）（顺铂）是一种强效抗肿瘤药物，其作用靶点是细胞DNA。在DNA与顺铂的反应中，会形成共价链内和链间交联（ICL）。最近已发表了ICL的两种溶液结构。在这两种模型中，双螺旋都发生了弯曲和解旋，但角度值有显著差异。我们利用铂的反常散射（MAD）作为唯一的相位信息来源，解析了含有单个顺铂ICL的双链DNA十聚体在100K时的晶体结构。我们发现双螺旋弯曲角度为47度，解旋角度为70度，这与之前的电泳分析结果一致。晶体通过分子间相互作用得以稳定，这种相互作用涉及从双螺旋中挤出的两个胞嘧啶，其中一个与末端的G.C对形成三联体。铂的配位几乎呈正方形，铂残基嵌入由九个水分子构成的笼中，这些水分子通过其他水分子与交联的鸟嘌呤、两个胺基以及磷酸二酯主链相连。结合ICL的化学稳定性对这种水分子组织进行了讨论。
