Kopka M L, Yoon C, Goodsell D, Pjura P, Dickerson R E
J Mol Biol. 1985 Jun 25;183(4):553-63. doi: 10.1016/0022-2836(85)90171-8.
The antitumor antibiotic netropsin has been co-crystallized with a double-helical B-DNA dodecanucleotide of sequence: C-G-C-G-A-A-T-T-BrC-G-C-G, and the structure of the complex has been solved by X-ray diffraction at a resolution of 2.2 A. The structure has been refined independently by Jack-Levitt and Hendrickson-Konnert least-squares methods, leading to a final residual error of 0.257 by the Jack-Levitt approach (0.211 for two-sigma data) or 0.248 by the Hendrickson-Konnert approach, with no significant difference between refined structures. The netropsin molecule displaces the spine of hydration and fits snugly within the minor groove in the A-A-T-T center. It widens the groove slightly and bends the helix axis back by 8 degrees, but neither unwinds nor elongates the double helix. The drug molecule is held in place by amide NH hydrogen bonds that bridge adenine N-3 and thymine O-2 atoms, exactly as with the spine of hydration. The requirement of A X T base-pairs in the binding site arises because the N-2 amino group of guanine would demand impermissibly close contacts with netropsin. It is proposed that substitution of imidazole for pyrrole in netropsin should create a family of "lexitropsins" capable of reading G X C-containing base sequences.
抗肿瘤抗生素纺锤菌素已与序列为C-G-C-G-A-A-T-T-BrC-G-C-G的双螺旋B-DNA十二聚核苷酸共结晶，并且该复合物的结构已通过分辨率为2.2埃的X射线衍射解析。该结构已分别通过杰克-莱维特和亨德里克森-科纳特最小二乘法进行精修，采用杰克-莱维特方法得到的最终残余误差为0.257（对于2σ数据为0.211），采用亨德里克森-科纳特方法得到的最终残余误差为0.248，精修后的结构之间无显著差异。纺锤菌素分子取代了水化层并紧密地契合于A-A-T-T中心的小沟内。它使小沟略有变宽，并使螺旋轴向后弯曲8度，但既不使双螺旋解旋也不使其伸长。药物分子通过酰胺NH氢键固定在位，这些氢键连接腺嘌呤的N-3和胸腺嘧啶的O-2原子，与水化层的情况完全相同。结合位点中需要A×T碱基对是因为鸟嘌呤的N-2氨基与纺锤菌素的接触会过于紧密而不合理。有人提出，在纺锤菌素中用咪唑取代吡咯应能产生一系列能够识别含G×C碱基序列的“离去菌素”。
