Structural Basis of Telomeric RNA Quadruplex-Acridine Ligand Recognition
Structural Basis of Telomeric RNA Quadruplex-Acridine Ligand Recognition
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DOI：
10.1021/ja109767y
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发表时间：
2011-03-02
影响因子：
15
通讯作者：
Neidle, Stephen
中科院分区：
文献类型：
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作者：
Collie, Gavin W.;Sparapani, Silvia;Neidle, Stephen
现在已知人类端粒DNA被转录成非编码RNA序列，称为TERRA。这些序列被认为在端粒功能的调节中起作用，可以形成高阶四链体结构，并且它们本身可以是治疗干预的靶点。本文报道了一种TERRA四链体-吖啶小分子复合物的晶体结构，其分辨率为2.60埃，并与类似的DNA四链体复合物的结构形成明显的对比。双分子RNA复合物具有螺旋桨样UUA环的平行链拓扑结构。这些环通过涉及核糖核苷酸糖的O2'羟基的多个氢键保持特定的构象，并在吖啶分子与RNA四链体的结合中发挥积极作用。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（牧羊犬，G. W的; Haider，S. M.; Neidle，S.; Parkinson，G. N. Nucleic Acids Res.2010，38，5569-5580），其对靶向TERRA四链体和更一般地RNA四链体的小分子的未来设计具有影响。
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 angstrom, s 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 quadruple): 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.