Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate
Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate
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DOI：
10.1002/anie.200503822
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Coll, M
中科院分区：
文献类型：
--
作者：
Oleksi, A;Blanco, AG;Coll, M
1249安吉。2006，118，1249-1253 2006 Wiley-VCH Verlag GmbH & Co. KGaA，来源于魏因海姆病。事实上，DNA已经是广泛使用的抗癌分子，如嵌入剂和铂类药物的目标;因此，DNA识别领域吸引了很多兴趣。现有的与DNA结合的合成试剂基本上以五种不同的模式之一进行：[1]它们与DNA碱基共价结合（或通过配位键）（如顺铂），插入碱基之间，结合在大沟中（通常与碱基形成氢键），结合在小沟中（如聚酰胺沟结合剂），或结合到糖-磷酸骨架上。尽管许多努力重新设计其化学结构并缩小其与特定DNA序列的结合能力，但DNA结合药物（特别是已进入临床的那些）通常是具有广泛细胞毒性作用的非特异性药物。与严格的序列识别相比，识别特定的不寻常DNA结构的能力是获得特异性的一个有吸引力的替代方案。在这里，我们提出了一个全新的模式的DNA识别，通过原子分辨率的X-射线晶体结构的三路DNA结在复杂的合成tetracationic超分子螺旋，完全适合到centraltagonal疏水腔的DNA结。这不仅是没有先例的DNA识别模式，但揭示了一个三向DNA连接作为一个明确的潜在结构目标的新的，高度特异性的药物。DNA连接是独特的分支结构，由几条双链会聚在一个点上组成。最具特征的DNA连接是四向连接，也称为霍利迪连接，是同源重组的关键中间体。[2]自由的四路DNA连接[3]和与蛋白质的不同复合物的三维结构已经解决。[4]相比之下，三通接头，虽然是最简单和最丰富的核酸分支结构，没有那么好地表征。在RNA和DNA中都存在三向连接。在RNA中，它们参与重要的生物学功能，如剪接[5]和翻译[6]，在DNA中，它们在DNA复制过程中短暂形成（复制叉）。[7]它们也是三联体重复扩增过程中的中间结构，[8]与几种人类遗传疾病相关的异常，如强直性肌营养不良1型和亨廷顿病。[9]三向连接存在于某些病毒基因组的反向末端重复序列中[10]，并且是噬菌体遗传重组过程中的中间体。[11]受自然界的启发，我们一直在探索一种新的方法，通过设计具有类似的纳米级分子表面的生物分子DNA识别基序的代理人，合成DNA识别。[12特别是，我们已经使用金属超分子化学来产生纳米级合成试剂，例如四价阳离子超分子螺旋酸盐（图1a）[Fe 2L 3] 4+，其由包裹在两个Fe 2+离子周围的三个双吡啶亚胺有机链形成。我们先前已经描述了这种试剂与天然聚合DNA的结合以及由此产生的显著的分子内DNA卷曲。[12]为了获得更多的信息，我们一直在尝试用寡核苷酸结晶该试剂。本文报道了一种含有DNA回文六核苷酸的复合物：5 '-d-（CGTACG）-3'。令我们惊讶的是，我们观察到的分子识别不是双链DNA，而是一个单一的DNA结构，一个三向连接（图1b），它定义了一个独特的三角形结构。
1249 Angew. Chem. 2006, 118, 1249–1253 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim disease at the source. Indeed, DNA is already the target for widely used anticancer molecules such as intercalators and platinum drugs; consequently the field of DNA recognition has attracted much interest. Existing synthetic agents that bind to DNA do so essentially in one of five distinct modes:[1] They bind covalently (or through coordination bonds) to the DNA bases (as cisplatin), intercalate between the bases, bind in the major groove (often with formation of hydrogen bonds to the bases), bind in the minor groove (as polyamide groove binders), or bind to the sugar–phosphate backbone. In spite of many efforts to redesign their chemical structure and narrow down their binding capacities to specific DNA sequences, DNA-binding drugs (particularly those which have reached the clinic) are, in general, nonspecific drugs with broad cytotoxic effects. The ability to recognize a specific unusual DNA structure—in contrast to strict sequence recognition—is an attractive alternative for gaining specificity. Herein we present a completely new mode of DNA recognition through an atomic resolution X-ray crystal structure of a three-way DNA junction in complex with a synthetic tetracationic supramolecular helicate that fits perfectly into the centraltrigonal hydrophobic cavity of the DNA junction. This is not only without precedent as a mode of DNA recognition, but reveals a three-way DNA junction as a well-defined potential structural target for novel, highly specific drugs. DNA junctions are unique branched structures that consist of several double strands converging at one point. The best-characterized DNA junction is the four-way junction, also known as a Holliday junction, a key intermediate in homologous recombination.[2] Three-dimensional structures of free four-way DNA junctions [3] and different complexes with proteins have been solved.[4] In contrast, three-way junctions, although being the simplest and most abundant nucleic acid branched structures, are not so well characterized. Three-way junctions occur both in RNA and DNA. In RNA they are involved in crucial biological functions such as splicing [5] and translation,[6] and in DNA they are formed transiently during DNA replication (the replication fork).[7] They are also intermediate structures during triplet repeat expansions,[8] anomalies associated with several human genetic diseases such as myotonic dystrophy type1 and Huntington s disease.[9] Three-way junctions are present in the inverted terminal repeats of certain viral genomes [10] and are intermediates during phage genetic recombination.[11] Inspired by nature, we have been exploring a new approach for synthetic DNA recognition through the design of agents that possess similar nanoscale molecular surfaces to those of biomolecular DNA-recognition motifs.[12, 13] In particular, we have used metallosupramolecular chemistry to generate nanoscale synthetic agents, such as the tetracationic supramolecular helicate (Figure1a)[Fe2L3] 4+, which is formed from three bis-pyridylimine organic strands wrapped about two Fe2+ ions. We have previously described the binding of this agent to natural polymeric DNAs and the remarkable intramolecular DNA coiling that results.[12] To gain more information we have been attempting to crystallize the agent with oligonucleotides. We report herein the complex with a DNA palindromic hexanucleotide: 5’-d-(CGTACG)-3’. To our surprise, we observe molecular recognition not of duplex DNA but rather of a singular DNA structure, a three-way junction (Figure 1b), which defines a unique triangular-shaped …