Kamitori S, Takusagawa F
X-ray Crystallography Laboratory, University of Kansas, Lawrence 66045-0046.
J Mol Biol. 1992 May 20;225(2):445-56. doi: 10.1016/0022-2836(92)90931-9.
The crystal structures of the 2:1 complex of the self-complementary DNA octamer d(GAAGCTTC) with actinomycin D has been determined at 3.0 A resolution. This is the first example of a crystal structure of a DNA-drug complex in which the drug intercalates into the middle of a relatively long DNA segment. The results finally confirmed the DNA-actinomycin intercalation model proposed by Sobell & co-workers in 1971. The DNA molecule adopts a severely distorted and slightly kinked B-DNA-like structure with an actinomycin D molecule intercalated in the middle sequence, GC. The two cyclic depsipeptides, which differ from each other in overall conformation, lie in the minor groove. The complex is further stabilized by forming base-peptide and chromophore-backbone hydrogen bonds. The DNA helix appears to be unwound by rotating one of the base-pairs at the intercalation site. This single base-pair unwinding motion generates a unique asymmetrically wound helix at the binding site of the drug, i.e. the helix is loosened at one end of the intercalation site and tightened at the other end. The large unwinding of the DNA by the drug intercalation is absorbed mostly in a few residues adjacent to the intercalation site. The asymmetrical twist of the DNA helix, the overall conformation of the two cyclic depsipeptides and their interaction mode with DNA are correlated to each other and rationally explained.
已在3.0埃分辨率下测定了自互补DNA八聚体d(GAAGCTTC)与放线菌素D的2:1复合物的晶体结构。这是DNA-药物复合物晶体结构的首个实例，其中药物嵌入相对较长DNA片段的中间。这些结果最终证实了索贝尔及其同事在1971年提出的DNA-放线菌素嵌入模型。DNA分子呈现出严重扭曲且略有扭结的类B-DNA结构，放线菌素D分子嵌入中间序列GC处。两个环缩肽在整体构象上彼此不同，位于小沟中。该复合物通过形成碱基-肽和发色团-主链氢键而进一步稳定。DNA螺旋似乎通过旋转嵌入位点处的一个碱基对而解开。这种单碱基对的解旋运动在药物结合位点产生了独特的不对称缠绕螺旋，即螺旋在嵌入位点的一端松开而在另一端收紧。药物嵌入导致的DNA的大量解旋主要被嵌入位点附近的少数残基吸收。DNA螺旋的不对称扭曲、两个环缩肽的整体构象及其与DNA的相互作用模式相互关联并得到合理解释。
