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首页> 美国卫生研究院文献>Nucleic Acids Research >Structures of m-iodo Hoechst–DNA complexes in crystals with reduced solvent content: implications for minor groove binder drug design
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Structures of m-iodo Hoechst–DNA complexes in crystals with reduced solvent content: implications for minor groove binder drug design

机译：溶剂含量降低的晶体中间碘的Hoechst-DNA复合物的结构：对小沟结合剂药物设计的影响

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摘要

The DNA photosensitisers m-iodo Hoechst and m-iodo, p-methoxy Hoechst have been co-crystallised with the oligonucleotide d(CGCGAATTCGCG)2 and their crystal structures determined. The crystals were then subjected to slow dehydration, which reduced their solvent contents from 40 (normal) to 30 (partially dehydrated) and then 20% (fully dehydrated) and caused a reduction in cell volume from 68 000 to 60 000 then 51 000 Å3. The dehydration resulted in a dramatic enhancement of diffraction resolution from ~2.6 to beyond 1.5 Å. Crystal structures have also been determined for the partially and fully dehydrated states. The fully dehydrated crystals consist of an infinite polymeric network, in which neighbouring dodecamer duplexes are crosslinked through phosphate oxygens via direct bonding to bridging magnesium cations. This unique three-dimensional structure for DNA is described in detail in the following companion paper. The present paper details evidence from the sequence of crystal structures that the DNA is able to breathe locally, allowing the ligand to leave the minor groove, re-orient in the surrounding solvent medium and then re-enter the groove in a different orientation and location. The rearrangement of the minor groove binding ligands during the dehydration process mimics the binding behaviour of these ligands in solution and in vivo. We also present details of the DNA–ligand interactions that are consistent with a hydrogen atom abstraction mechanism for photocleavage of DNA.
机译：DNA光敏剂m-iodo Hoechst和m-iodo，对甲氧基Hoechst已与寡核苷酸d（CGCGAATTCGCG）2共结晶，并确定了它们的晶体结构。然后将晶体进行缓慢脱水，将其溶剂含量从40（正常）降低至30（部分脱水），然后降低20％（完全脱水），并使晶胞体积从68'000降低至60000，然后降低51000Å 3 。脱水导致衍射分辨率从〜2.6显着提高到超过1.5Å。还已经确定了部分和完全脱水状态的晶体结构。完全脱水的晶体由无限的聚合物网络组成，其中相邻的十二聚体双链体通过直接结合到桥连的镁阳离子上的磷酸氧而交联。 DNA的这种独特的三维结构将在以下随附的论文中详细介绍。本文从晶体结构的序列中详细证明了DNA能够局部呼吸，从而使配体离开较小的凹槽，在周围的溶剂介质中重新定向，然后以不同的方向和位置重新进入凹槽。 。脱水过程中小沟结合配体的重排模拟了溶液和体内这些配体的结合行为。我们还介绍了DNA与配体相互作用的细节，这些细节与DNA光裂解的氢原子抽象机制一致。

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