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Molecular dynamics analysis of mRNA capping: Characterising the activation mechanisms of the mammalian capping enzymes

mRNA 加帽的分子动力学分析：表征哺乳动物加帽酶的激活机制

基本信息

批准号：
1786154
负责人：
金额：
--
依托单位：
University of Dundee
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1786154
关键词：
Molecular dynamics analysis mRNA capping

项目摘要

mRNA capping is vital for the regulation of genes in eukaryotic organisms. This capping is activated downstream of c-Myc, a major oncoprotein overexpressed in over 50% of human cancers, therefore, mRNA capping is a promising target for cancer therapeutics. The Capping Enzyme carries out the first two steps in this process. Many questions remain about its activation and regulation, limiting our ability to design drugs that target it. It is activated by binding to the phosphorylated C-terminal Domain of RNA Polymerase II. However, the molecular details of this activation mechanism have been elusive using conventional biochemical techniques.I will address this problem from a new angle by using molecular dynamics simulations to study the conformational changes that occur upon C-terminal Domain binding. Further computational and biophysical analysis will be performed to characterise the interaction surface and catalytic core. An interdisciplinary collaboration with the Cowling lab will yield experimental evidence to support these findings.Key Words and Skills:Questions:1. Explain interdisciplinary interface: Yes, it talks about collaboration between computational biophysics and experimental biology2. Does project require significant amount of quantitative skills? YES3. Does project require significant amount of whole organism physiology skills? NO

mRNA 加帽对于真核生物中的基因调节至关重要。这种加帽在 c-Myc 下游被激活，c-Myc 是一种主要癌蛋白，在超过 50% 的人类癌症中过度表达，因此，mRNA 加帽是癌症治疗的一个有前途的靶标。封盖酶执行此过程中的前两个步骤。关于它的激活和调节仍然存在许多问题，限制了我们设计针对它的药物的能力。它通过与 RNA 聚合酶 II 的磷酸化 C 末端结构域结合而被激活。然而，使用传统的生化技术，这种激活机制的分子细节难以捉摸。我将通过使用分子动力学模拟来研究 C 端结构域结合时发生的构象变化，从一个新的角度解决这个问题。将进行进一步的计算和生物物理分析来表征相互作用表面和催化核心。与考林实验室的跨学科合作将产生支持这些发现的实验证据。关键词和技能：问题：1。解释跨学科接口：是的，它谈论计算生物物理学和实验生物学之间的合作2。项目是否需要大量的定量技能？是的3。该项目是否需要大量的整体有机体生理学技能？不