...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Structural Effects of the L145Q, V157F, and R282W Cancer-Associated Mutations in the p53 DNA-Binding Core Domain
【24h】

Structural Effects of the L145Q, V157F, and R282W Cancer-Associated Mutations in the p53 DNA-Binding Core Domain

机译：p53 DNA结合核心结构域中L145Q，V157F和R282W癌症相关突变的结构效应

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

The p53 tumor suppressor is a transcription factor involved in many important signaling pathways, such as apoptosis and cell-cycle arrest. In over half of human cancers, p53 function is compromised by a mutation in its gene. Mutations in the p53 DNA-binding core domain destabilize the structure and reduce DNA-binding activity. We performed molecular dynamics simulations at physiological temperature to study the structural and dynamic ef-ects of the L145Q, V157F, and R282W cancer-associated mutations in comparison to the wild-type protein. While there were common regions of destabilization in the mutant simulations, structural changes particular to individual mutations were also observed. Significant backbone deviations of the H2 helix and S7-S8 loop were observed in all mutant simulations; the H2 helix binds to DNA. In addition, the L145Q and V157F mutations, which are located in the beta-sandwich core of the domain, disrupted the beta-sheet structure and the loop sheet helix motif. The R282W mutation caused distortion of the loop sheet helix motif, but otherwise this mutant was similar to the wild-type structure. The introduction of these mutations caused rearrangement of the DNA-binding surface, consistent with their reduced DNA-binding activity. The simulations reveal detailed effects of the mutations on the stability and dynamics of p53 that may provide insight for therapeutic approaches.
机译：p53肿瘤抑制因子是一种转录因子，参与许多重要的信号通路，例如细胞凋亡和细胞周期停滞。在超过一半的人类癌症中，p53功能因其基因突变而受损。 p53 DNA结合核心结构域中的突变使结构不稳定并降低DNA结合活性。我们在生理温度下进行了分子动力学模拟，以研究与野生型蛋白相比L145Q，V157F和R282W癌症相关突变的结构和动态效应。尽管在突变模拟中存在不稳定的常见区域，但也观察到了特定于单个突变的结构变化。在所有突变模拟中均观察到H2螺旋和S7-S8环的显着骨架偏差。 H2螺旋与DNA结合。此外，位于该结构域的β-三明治核心的L145Q和V157F突变破坏了β-折叠结构和环片螺旋基序。 R282W突变引起环片螺旋基序变形，但除此之外，该突变体与野生型结构相似。这些突变的引入引起DNA结合表面的重排，与其降低的DNA结合活性一致。模拟揭示了突变对p53的稳定性和动力学的详细影响，可为治疗方法提供见识。

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