Adaptive and Specific Recognition of Telomeric G-Quadruplexes via Polyvalency Induced Unstacking of Binding Units,Journal of the American Chemical Society

当前位置： X-MOL 学术 › J. Am. Chem. Soc. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Adaptive and Specific Recognition of Telomeric G-Quadruplexes via Polyvalency Induced Unstacking of Binding Units
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2017-05-15 00:00:00 , DOI: 10.1021/jacs.7b00607
Jibin Abraham Punnoose ₁ , Yue Ma ₂ , Yuanyuan Li ₁ , Mai Sakuma ₂ , Shankar Mandal ₁ , Kazuo Nagasawa ₂ , Hanbin Mao ₁

Affiliation

Targeting DNA G-quadruplexes using small-molecule ligands has shown to modulate biological functions mediated by G-quadruplexes inside cells. Given >716 000 G-quadruplex hosting sites in human genome, the specific binding of ligands to quadruplex becomes problematic. Here, we innovated a polyvalency based mechanism to specifically target multiple telomeric G-quadruplexes. We synthesized a tetrameric telomestatin derivative and evaluated its complex polyvalent binding with multiple G-quadruplexes by single-molecule mechanical unfolding in laser tweezers. We found telomestatin tetramer binds to multimeric telomeric G-quadruplexes >40 times stronger than monomeric quadruplexes, which can be ascribed to the polyvalency induced unstacking of binding units (or PIU binding) for G-quadruplexes. While stacking of telomestatin units in the tetramer imparts steric hindrance for the ligand to access stand-alone G-quadruplexes, the stacking disassembles to accommodate the potent polyvalent binding between the tetramer ligand and multimeric G-quadruplexes. We anticipate this adaptive PIU binding offers a generic mechanism to selectively target polymeric biomolecules prevalent inside cells.

中文翻译：

端粒G四元体通过多价诱导结合单元的堆积的自适应和特异性识别。

使用小分子配体靶向DNA G-四链体已显示可调节细胞内G-四链体介导的生物学功能。考虑到人类基因组中超过71.6万个G-四链体宿主位点，配体与四链体的特异性结合变得成问题。在这里，我们创新了一种基于多价的机制，专门针对多个端粒G-四链体。我们合成了一个四聚体的telomestatin衍生物，并通过激光镊子中的单分子机械展开法评估了其与多个G-四链体的复杂多价结合。我们发现端粒他汀四聚体与多聚端粒G-四链体的结合强度比单体四链体强40倍以上，这可以归因于多价诱导的G-四链体结合单元的解叠（或PIU结合）。在四聚体中端粒他汀单元的堆叠为配体进入独立的G-四链体提供了空间位阻，而堆叠则解体以适应四聚体配体与多聚体G-四链体之间的有效多价结合。我们预期这种自适应PIU结合提供了一种通用机制，可以选择性地靶向细胞内普遍存在的聚合物生物分子。

更新日期：2017-05-26

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11