Understanding the Ligand Binding by Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Histone Demethylases

项目摘要 表观遗传调控中最重要的工具之一是通过组蛋白的去甲基化 proteins.最丰富的组蛋白脱甲基酶属于非血红素铁和2-酮戊二酸- (2OG)依赖性JmjC-亚家族，催化Nε-甲基赖氨酸残基的去甲基化， 组蛋白KDM 4A和KDM 7 B是Fe（II）和2 OG依赖的组蛋白赖氨酸脱甲基酶 与各种癌症有关，如前列腺癌，乳腺癌，喉癌， 胃癌和子宫内膜癌。 目前的建议结合了多尺度计算方法与先进的光谱 技术来阐明两个之间在原子和电子结构水平上的差异 非血红素Fe（II）和2-酮戊二酸（2 OG）依赖性组蛋白脱甲基酶（KDM）：KDM 4A i）共底物-20G，H3组蛋白和双氧的结合;和ii） 结合位点、第二球体和更远的球体之间的长程相关运动 这些蛋白质区域对结合过程至关重要。我们知识上的差距 基础不能通过实验或计算方法孤立地解决。 拟议的研究将告知原子方面的偏好KDM 4A的三- 甲基化赖氨酸残基和KDM 7 B对二-和单-甲基化赖氨酸的转化。研究 将阐明为什么KDM 4A能够结合精氨酸残基并使其脱甲基化，而KDM 4A则相反。 KDM7B 这项研究将缩小关于如何改变蛋白质环境的知识差距， KDM选择性地稳定重要的物种沿着形成完整的催化剂。 生产性酶-底物复合物。该研究还将确定特定的远程 关键结合残基与第二球残基和更长距离的相关运动 蛋白质区域。预期这种相关的相互作用是酶选择性的， 为酶选择性表观遗传药物的设计提供了新的机会。一个令人兴奋 研究计划的一个方面是，它将提供一个独特的动机本科生 利用现代计算和实验技术从事顶级研究的机会 符合学术研究促进奖的使命的方法。

PROJECT SUMMARY One of the most important tools in epigenetic regulation is through demethylation of histone proteins. The most abundant histone demethylases belong to non-heme iron and 2- oxoglutarate- (2OG) dependent JmjC- subfamily that catalyze the demethylation of Nε-methyllysine residues in histone proteins. KDM4A and KDM7B are Fe (II) and 2OG-dependant histone lysine demethylase that have been linked to various forms of cancer such as prostate cancer, breast cancer, laryngeal, gastric and endometrial carcinoma. The current proposal combines multiscale computational methods with advanced spectroscopic techniques to elucidate the differences at atomistic and electronic structural levels between two non-heme Fe (II) and 2-oxoglutarate (2OG)-dependent histone demethylases (KDMs): KDM4A and KDM7B in respect to: i) the binding of co-substrates - 2OG, H3 histone and dioxygen; and ii) the long-range correlated motions between the binding site, second sphere and more distant protein regions that are in crucial importance for the binding process. This gap in our knowledge base cannot be resolved through either experimental or computational approaches in isolation. The proposed research will inform on the atomistic aspects of the preference of KDM4A for tri- methylated lysine residues and of KDM7B towards di- and mono-methylated lysines. The study will elucidate why KDM4A is able to bind and demethylate arginine residues in contrast to KDM7B. This research will close the knowledge gap about how altered protein environments in the two KDMs selectively stabilize the important species along the formation of the complete catalytically productive enzyme-substrate complex. The research will also identify specific long-range correlated motions of key binding residues with a second sphere residues and longer-distant protein regions. Such correlated interactions are expected to be enzyme-selective which will provide novel opportunities for the design of enzyme-selective epigenetic drugs. An exciting aspect of the research plan is that it will provide motivated undergraduate students with a unique opportunity to engage in top class research using modern computational and experimental methods in line with the mission of the Academic Research Enhancement Award.