• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular Biology >Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States
【24h】

Demonstration that Small Molecules can Bind and Stabilize Low-abundance Short-lived RNA Excited Conformational States

机译：小分子可以结合和稳定低丰度短寿命的RNA激发的构象状态的示范

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Many promising RNA drug targets have functions that require the formation of RNA-protein complexes, but inhibiting RNA-protein interactions can prove difficult using small molecules. Regulatory RNAs have been shown to transiently form excited conformational states (ESs) that remodel local aspects of secondary structure. In some cases, the ES conformation has been shown to be inactive and to be poorly recognized by protein binding partners. In these cases, specifically targeting and stabilizing the RNA ES using a small molecule provides a rational structure-based strategy for inhibiting RNA activity. However, this requires that a small molecule discriminates between two conformations of the same RNA to preferentially bind and stabilize the short-lived low-abundance ES relative to the long-lived more abundant ground state (GS). Here, we tested the feasibility of this approach by designing a mutant that inverts the conformational equilibrium of the HIV-1 transactivation response element (TAR) RNA, such that the native GS conformation becomes a low-abundance ES. Using this mutant and NMR chemical shift mapping experiments, we show that argininamide, a ligand mimic of TAR's cognate protein binding partner Tat, is able to restore a native-like conformation by preferentially binding and stabilizing the transient and low-populated ES. A synthetic small molecule optimized to bind the TAR GS also partially stabilized the ES, whereas an aminoglycoside molecule that binds RNAs nonspecifically did not preferentially stabilize the ES to a similar extent. These results support the feasibility of inhibiting RNA activity using small molecules that preferentially bind and stabilize the ES. (C) 2019 Elsevier Ltd. All rights reserved.
机译：许多有前途的RNA药物靶标具有需要形成RNA-蛋白质复合物的功能，但抑制RNA-蛋白质相互作用可以使用小分子证明困难。调节RNA已经显示为瞬时形成兴奋的构象状态（ESS），其重组次级结构的局部方面。在某些情况下，ES构象已被证明是不活跃的，并且蛋白质结合伴侣识别不良。在这些情况下，使用小分子特别靶向和稳定RNA ES提供了抑制RNA活性的基于基于结构的策略。然而，这要求小分子在相同RNA的两个构象之间判别，以优先结合和稳定相对于长寿命的更丰富的地面状态（GS）的短寿命的低丰度ES。在这里，我们通过设计反转HIV-1转移响应元件（焦油）RNA的构象平衡的突变体来测试该方法的可行性，使得天然GS构象变为低丰度。使用该突变体和NMR化学换档测绘实验，我们表明焦油的同源蛋白结合配偶体TAT的氨基酰胺是一种焦油，通过优先结合和稳定瞬态和低人口的ES来恢复天然样构象。优化以结合焦油GS的合成小分子也部分稳定，而结合RNA的氨基糖苷类分子不优先稳定ES至类似程度。这些结果支持使用优先结合和稳定ES的小分子抑制RNA活性的可行性。 （c）2019 Elsevier Ltd.保留所有权利。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号