Engineering the quadruplex fold: Nucleoside conformation determines both folding topology and molecularity in guanine quadruplexes
Engineering the quadruplex fold: Nucleoside conformation determines both folding topology and molecularity in guanine quadruplexes
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DOI：
10.1021/ja0603958
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发表时间：
2006-05-03
影响因子：
15
通讯作者：
Shafer, RH
中科院分区：
文献类型：
--
作者：
Tang, CF;Shafer, RH
以鸟嘌呤四重链为基础的核酸四重链，根据序列的不同，可以由一条或多条链产生。由单链组成的鸟嘌呤通常折叠成两种主要拓扑结构之一：反平行，其中所有或一半的鸟嘌呤延伸是彼此反平行的，或平行，其中所有鸟嘌呤延伸是彼此平行的。在后者中，所有鸟嘌呤核苷都具有糖苷键的反构象，而在前者中，一半具有反构象，一半具有正构象。虽然反平行折叠是更常见的折叠，但生物学上重要的平行四联体的例子正变得越来越普遍。因此，了解决定四重折叠的力是很有意义的。在这里，我们通过rG选择性取代dG来研究单个核苷构象对整体折叠拓扑结构的影响。我们可以通过这种方法逆转凝血酶结合适体（TBA）的反平行折叠。此外，这种取代将单分子四联体转化为双分子四联体。在TBA的全rna类似物中，类似的反向取代导致拓扑结构的平行或反平行变化，并将链结构从双分子变为单分子。根据所做的特定取代，我们得出结论，鸟嘌呤核糖核苷对反构象的强烈偏好是拓扑结构变化的驱动力。这些结果证明了鸟嘌呤核苷的构象性质不仅控制四重折叠拓扑结构，而且影响四重分子结构，并提供了一种控制这些性质的方法。
Nucleic acid quadruplexes, based on the guanine quartet, can arise from one or several strands, depending on the sequence. Those consisting of a single strand are usually folded in one of two principal topologies: antiparallel, in which all or half of the guanine stretches are antiparallel to each other, or parallel, in which all guanine stretches are parallel to each other. In the latter, all guanine nucleosides possess the anti conformation about the glycosidic bond, while in the former, half possess the anti conformation, and half possess the syn conformation. While antiparallel is the more common fold, examples of biologically important, parallel quadruplexes are becoming increasingly common. Thus, it is of interest to understand the forces that determine the quadruplex fold. Here, we examine the influence of individual nucleoside conformation on the overall folding topology by selective substitution of rG for dG. We can reverse the antiparallel fold of the thrombin binding aptamer (TBA) by this approach. Additionally, this substitution converts a unimolecular quadruplex into a bimolecular one. Similar reverse substitutions in the all-RNA analogue of TBA result in a parallel to antiparallel change in topology and alter the strand configuration from bimolecular to unimolecular. On the basis of the specific substitutions made, we conclude that the strong preference of guanine ribonucleosides for the anti conformation is the driving force for the change in topology. These results demonstrate how conformational properties of guanine nucleosides govern not only the quadruplex folding topology but also impact quadruplex molecularity and provide a means to control these properties.