Solution structure of a HNA-RNA hybrid
Solution structure of a HNA-RNA hybrid
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DOI：
10.1016/s1074-5521(00)00017-x
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发表时间：
2000-09-01
影响因子：
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通讯作者：
Herdewijn, P
中科院分区：
文献类型：
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作者：
Lescrinier, E;Esnouf, R;Herdewijn, P
背景资料：具有构象受限的糖-磷酸骨架的合成核酸类似物广泛用于生物医学和生物化学应用的反义策略中。修饰的骨架保护寡核苷酸免于在活细胞内降解，这允许它们与靶mRNA中的序列形成稳定的双链体，目的是阻止它们的翻译。生物活性最高的反义寡核苷酸还通过激活内源性RNA酶H触发靶RNA的切割。合成寡核苷酸也进行了系统的研究，以描绘的起源的手性的DNA和RNA都是由D-nucleosides.Results组成：己糖醇核酸（HNA）是第一个例子的寡核苷酸与一个六元碳水化合物部分，可以强烈地结合，并选择性地互补RNA寡聚体。我们提出了第一个高分辨率的HNA寡聚体结合到互补RNA链的核磁共振结构。HNA-RNA复合物形成反平行异源双链体，并采用属于A型家族的螺旋构象。可能是由于六元环的刚性椅构象的刚性，双链体中的HNA和RNA链都是明确限定的。观察到的末端磨损效应的情况下，也表明降低了构象的灵活性的RNA-RNA双链体相比，典型的dsRNA或RNA-DNA duplex.Conclusions：P-P的距离横跨小沟，这是接近A-型，和刚性构象的HNA-RNA复合物，解释其抵抗降解RNase H。HNA-RNA双链体的A型特征和HNA链的柔性降低可能是HNA模板在寡核苷酸的非酶复制中的立体选择性的原因，支持具有六元环的核苷可能存在于分子进化的某个阶段的理论。
Background: Synthetic nucleic acid analogues with a conformationally restricted sugar-phosphate backbone are widely used in antisense strategies for biomedical and biochemical applications. The modified backbone protects the oligonucleotides against degradation within the living cell, which allows them to form stable duplexes with sequences in target mRNAs with the aim of arresting their translation. The biologically most active antisense oligonucleotides also trigger cleavage of the target RNA through activation of endogenous RNase H. Systematic studies of synthetic oligonucleotides have also been conducted to delineate the origin of the chirality of DNA and RNA that are both composed of D-nucleosides.Results: Hexitol nucleic acids (HNA) are the first example of oligonucleotides with a six-membered carbohydrate moiety that can bind strongly and selectively to complementary RNA oligomers. We present the first high resolution nuclear magnetic resonance structure of a HNA oligomer bound to a complementary RNA strand. The HNA-RNA complex forms an anti-parallel heteroduplex and adopts a helical conformation that belongs to the A-type family, Possibly, due to the rigidity of the rigid chair conformation of the six-membered ring both the HNA and RNA strand in the duplex are well defined. The observed absence of end-fraying effects also indicate a reduced conformational flexibility of the RNA-RNA duplex compared to canonical dsRNA or an RNA-DNA duplex.Conclusions: The P-P distance across the minor groove, which is close to A-form, and the rigid conformation of the HNA-RNA complex, explain its resistance towards degradation by Rnase H. The A-form character of the HNA-RNA duplex and the reduced flexibility of the HNA strand is possibly responsible for the stereoselectivity of HNA templates in non-enzymatic replication of oligonucleotides, supporting the theory that nucleosides with six-membered rings could have existed at some stage in molecular evolution.