Structure of a human telomeric DNA sequence stabilized by 8-bromoguanosine substitutions, as determined by NMR in a K+ solution
Structure of a human telomeric DNA sequence stabilized by 8-bromoguanosine substitutions, as determined by NMR in a K+ solution
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DOI：
10.1111/j.1742-4658.2007.05881.x
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发表时间：
2007-07-01
期刊：
影响因子：
5.4
通讯作者：
Katahira, Masato
中科院分区：
文献类型：
--
作者：
Matsugami, Akimasa;Xu, Yan;Katahira, Masato
人类端粒DNA的结构是有争议的，它取决于序列的背景和用于确定它的方法。在K+存在下的溶液结构是特别有趣的，但由于可能的构象异质性，该结构尚未被阐明。在这里，一个独特的策略是应用于稳定一个这样的结构在K+溶液中取代鸟苷与8-溴鸟苷在适当的位置。由此产生的光谱更清晰，并导致在高原子分辨率下确定结构。这表明，8-溴鸟苷的应用是一个强有力的工具，以克服困难的核酸结构测定所产生的构象异质性。所获得的结构是混合平行/反平行四链体。最近在另一项研究中报道了端粒DNA的结构，其中通过突变和所得的额外相互作用实现稳定化[Luu KN，Phan AT，Kuryavyi V，Lacroix L & Patel DJ（2006）K+溶液中的人端粒的结构：分子内（3+1）G-四链体支架。J Am Chem Soc 128，9963-9970]。两者的鸟嘌呤束结构相似。然而，在连接鸟嘌呤束的环中观察到了差异，这可能在端粒的高阶排列中起作用。我们的结构可以用来设计一个小分子，稳定的四链体。这种类型的分子被认为抑制端粒酶，因此有望成为候选抗癌药物。
The structure of human telomeric DNA is controversial; it depends upon the sequence contexts and the methodologies used to determine it. The solution structure in the presence of K+ is particularly interesting, but the structure is yet to be elucidated, due to possible conformational heterogeneity. Here, a unique strategy is applied to stabilize one such structure in a K+ solution by substituting guanosines with 8-bromoguanosines at proper positions. The resulting spectra are cleaner and led to determination of the structure at a high atomic resolution. This demonstrates that the application of 8-bromoguanosine is a powerful tool to overcome the difficulty of nucleic acid structure determination arising from conformational heterogeneity. The obtained structure is a mixed-parallel/antiparallel quadruplex. The structure of telomeric DNA was recently reported in another study, in which stabilization was brought about by mutation and resultant additional interactions [Luu KN, Phan AT, Kuryavyi V, Lacroix L & Patel DJ (2006) Structure of the human telomere in K+ solution: an intramolecular (3+1) G-quadruplex scaffold. J Am Chem Soc 128, 9963-9970]. The structure of the guanine tracts was similar between the two. However, a difference was seen for loops connecting guanine tracts, which may play a role in the higher order arrangement of telomeres. Our structure can be utilized to design a small molecule which stabilizes the quadruplex. This type of molecule is supposed to inhibit a telomerase and thus is expected to be a candidate anticancer drug.