CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, London, United Kingdom.
J Am Chem Soc. 2011 Mar 2;133(8):2721-8. doi: 10.1021/ja109767y. Epub 2011 Feb 3.
Human telomeric DNA is now known to be transcribed into noncoding RNA sequences, termed TERRA. These sequences, which are believed to play roles in the regulation of telomere function, can form higher-order quadruplex structures and may themselves be the target of therapeutic intervention. The crystal structure of a TERRA quadruplex-acridine small-molecule complex at a resolution of 2.60 Å, is reported here and contrasts remarkably with the structure of the analogous DNA quadruplex complex. The bimolecular RNA complex has a parallel-stranded topology with propeller-like UUA loops. These loops are held in particular conformations by multiple hydrogen bonds involving the O2' hydroxyl groups of the ribonucleotide sugars and play an active role in binding the acridine molecules to the RNA quadruplex. By contrast, the analogous DNA quadruplex complex has simpler 1:1 acridine binding, with no loop involvement. There are significant loop conformational changes in the RNA quadruplex compared to the native TERRA quadruplex (Collie, G. W.; Haider, S. M.; Neidle, S.; Parkinson, G. N. Nucleic Acids Res. 2010, 38, 5569 - 5580), which have implications for the future design of small molecules targeting TERRA quadruplexes, and RNA quadruplexes more generally.
人类端粒 DNA 现在已知被转录为非编码 RNA 序列，称为 TERRA。这些序列被认为在调节端粒功能中发挥作用，能够形成更高阶的四链体结构，并且本身可能成为治疗干预的目标。本文报道了一个分辨率为 2.60 Å 的 TERRA 四链体-吖啶小分子复合物的晶体结构，与类似的 DNA 四链体复合物的结构形成了鲜明对比。双分子 RNA 复合物具有平行链拓扑结构和推进器样的 UUA 环。这些环通过涉及核糖核苷酸糖的 O2' 羟基的多个氢键保持在特定构象，并在将吖啶分子结合到 RNA 四链体中发挥积极作用。相比之下，类似的 DNA 四链体复合物具有更简单的 1:1 吖啶结合，没有环参与。与天然 TERRA 四链体相比，RNA 四链体中的环构象变化很大（Collie，G.W.；Haider，S.M.；Neidle，S.；Parkinson，G.N. Nucleic Acids Res. 2010，38，5569-5580），这对未来设计靶向 TERRA 四链体的小分子以及更一般的 RNA 四链体具有重要意义。
