Smith C K, Davies G J, Dodson E J, Moore M H
Department of Chemistry, University of York, Heslington, England.
Biochemistry. 1995 Jan 17;34(2):415-25. doi: 10.1021/bi00002a005.
The structure of the self-complementary deoxyoligonucleotide d5'(TGATCA) complexed with nogalamycin, an antitumor anthracycline, has been solved to 1.8 A resolution using X-ray crystallographic methods. The technique of single isomorphous replacement, utilizing the anomalous signal of bromine in derivative data collected at three different wavelengths, Cu K alpha, Mo K alpha, and 0.91 A synchroton radiation, was used. The complex crystallized in space group P4(1)2(1)2 with unit cell dimensions a = 37.2 A and c = 70.1 A. The final structure including 116 water molecules has an overall R factor of 19.5% for the 4767 reflections with F > or = 1 sigma F in the resolution range 10.0-1.8 A. One nogalamycin molecule intercalates between each of the d5'(TpG) steps at both ends of a distorted B DNA double helix. This structure provides the first three-dimensional picture of nogalamycin bound to the triplet sequence d5'(TGA), one of its favorable natural binding sites. The drug exhibits a strict requirement for binding to the 3' side of a pyrimidine and the 5' side of a purine. Nogalamycin has bulky sugar groups at either end of a planar aglycon chromophore; therefore, in order for intercalation to occur, the DNA must either transiently open or flex along the helix axis to allow insertion of the chromophore between the base pairs. Conformational change in nogalamycin is observed in the drug-DNA complex with respect to free nogalamycin. Nogalamycin binding to DNA induces severe deformation to the intercalation site base pairs. In comparison to previously reported anthracycline-DNA structures significant differences in base-pair geometry, drug hydrogen-bonding patterns, and the extent of hydration are observed. The position of the drug in this complex is stabilized by a number of nonbonded forces including van der Waals interactions and extensive direct and solvent-mediated hydrogen bonds to the DNA duplex.
采用X射线晶体学方法，已将与抗肿瘤蒽环类药物诺加霉素复合的自互补脱氧寡核苷酸d5′(TGATCA)的结构解析至1.8 Å分辨率。使用了单同晶置换技术，利用在三种不同波长（Cu Kα、Mo Kα和0.91 Å同步辐射）收集的衍生物数据中溴的异常信号。该复合物在空间群P4(1)2(1)2中结晶，晶胞尺寸a = 37.2 Å，c = 70.1 Å。最终结构包括116个水分子，对于分辨率范围为10.0 - 1.8 Å内F≥1σF的4767个反射，总体R因子为19.5%。一个诺加霉素分子插入到扭曲的B型DNA双螺旋两端的每个d5′(TpG)步之间。该结构提供了诺加霉素与三联体序列d5′(TGA)结合的首张三维图像，d5′(TGA)是其有利的天然结合位点之一。该药物对与嘧啶的3′侧和嘌呤的5′侧结合有严格要求。诺加霉素在平面苷元发色团的两端具有庞大的糖基；因此，为了发生嵌入，DNA必须沿螺旋轴瞬时打开或弯曲，以允许发色团插入碱基对之间。在药物 - DNA复合物中观察到诺加霉素相对于游离诺加霉素的构象变化。诺加霉素与DNA的结合会导致嵌入位点碱基对发生严重变形。与先前报道的蒽环类 - DNA结构相比，观察到碱基对几何形状、药物氢键模式和水合程度存在显著差异。该复合物中药物的位置通过多种非键合力得以稳定，包括范德华相互作用以及与DNA双链体的广泛直接和溶剂介导的氢键。
