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席真、周传政、彭谦合作研究成果:核糖构象决定RNA断裂速率
2018-10-12

通过分子内转酯过程的RNA断裂是一个涉及到RNA的加工成熟、代谢和功能调控的基本反应。对这一反应机理的深入研究,不仅可以加深我们对细胞中RNA相关生物过程的理解,还将促进以RNA为靶标的药物设计与开发。
核糖核苷酸(RNA)的核糖是呋喃糖,主要以South(S)和North(N)两种构象存在,这两种构象可以相互转换,但后者在热力学上更为稳定。最近,席真、周传政团队探讨了核糖构象对RNA断裂速率的影响。他们合成了两个核苷酸模型分子,U6,3′‑Methano和 U4’‑Me,并引入到RNA链中。在斯洛文尼亚国家核磁中心的Plavec教授的帮助下,通过核磁共振确定了U6,3′‑Methano和U4’‑Me分别被锁定在North和South构象。他们测定了RNA水解的速率,发现不同构象的RNA断裂速率具有如下规律:South锁定RNA>天然RNA>>North锁定RNA。断裂South构象锁定的RNA比断裂North构象锁定的RNA快100倍以上。彭谦课题组通过量化计算对该反应中糖环构象变化进行研究,证实了South构象过渡态 (Pathway II)在反应动力学上,较North构象的过渡态 (Pathway I)更有优势。其中P-O键的断裂为决速步,并揭示了反应机理可能由于糖环构象变化引发的碱基与Mg离子配位活化相关。因此天然RNA分子可以通过克服一个很小的能垒转变成热力学上不稳定的South构象,然后经过一个更为有利的South过渡态,实现RNA的断裂。该研究结果表明糖环构象对RNA断裂速率有非常显著的影响,这为深入理解细胞内RNA的断裂机制提供了新视角,对以RNA为靶标的药物设计具有理论指导意义。博士生郭丰敏为该论文第一作者,硕士生岳泽昆完成了量化计算部分,为论文第二作者。

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文章链接:https://pubs.acs.org/doi/10.1021/jacs.8b06313
      上述研究得到了中组部青年千人计划、国家自然科学基金委、天津市科委、南开大学以及元素有机化学国家重点实验室的资助。

[Zhen Xi,Chuanzheng Zhou and Qian Penggroup]
Ribose Conformation Modulates RNA Cleavage
     The RNA cleavage via internal transesterification is a fundamental reaction that is involved in RNA processing and metabolism, and the regulation thereof, but the mechanistic details have not been fully elucidated. Mechanistic studies will deepen our understanding not only of spontaneous RNA degradation under physiological conditions but also of ribozyme- and RNase-catalyzed RNA cleavage and splicing, and may facilitate the rational design of artificial ribonucleases for therapeutic RNA targeting.
     The ribose moieties in RNA mainly exist in two puckered conformations, designated North (N) and South (S), that are in equilibrium; the former is thermally more stable and thus predominates.The authorsintroduced U6,3′‑Methano and U4’‑Meinto oligonucleotides andconfirmed that they were constrained in North and South conformation respectively by NMR. RNA cleavage rates were found to decrease in the order South-constrained ribonucleotide > native ribonucleotide ≫North-constrained counterpart.DFT calculation results demonstrated that RNA cleavage via the S-type TS (Pathway II) is kinetically more favorable than via the N-type TS (Pathway I). Therefore, a rapid North to South conformational flip followed by internal transesterification via South transition states seems kinetically more favorable for RNA cleavage.The above-described results indicate that the ribose conformation plays an important role in modulating RNA cleavage via internal transesterification.
     These results shed light on the effect of ribose conformation on RNA cleavage via internal transesterification and can be expected to improve our understanding of the mechanism of RNA cleavage catalyzed by RNases and ribozymes as well. In addition, the principle revealed may facilitate the rational design of catalysts for site-specific RNA cleavage and functionalized RNA molecules for biomedical applications.