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

了解非血红素 Fe(II) 和 2-氧化戊二酸依赖性组蛋白去甲基酶的配体结合

基本信息

批准号：
10202877
负责人：
Christo Zhivkov Christov
金额：
$ 38.24万
依托单位：
MICHIGAN TECHNOLOGICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202877
关键词：
Academic Research Enhancement Awards Arginine Basic Science Binding Binding Sites Biochemistry Bioinorganic Chemistry Biological Process Biomedical Research Complex Computer Models Computing Methodologies Diffusion Dioxygen Distant Drug Design Endometrial Carcinoma Environment Enzymes Epigenetic Process Eukaryotic Cell Face Foundations Genetic Diseases Geometry Goals Histone H3 Histones Iron Knowledge Ligand Binding Link Lysine Malignant Neoplasms Malignant neoplasm of prostate Methods Methylation Mission Modernization Molecular Molecular Conformation Motion National Institute of General Medical Sciences Other Genetics Pathologic Processes Peptides Positioning Attribute Prevention Process Protein Region Proteins Research Site Specificity Stomach Carcinoma Structure Techniques Testing Triad Acrylic Resin United States National Institutes of Health alpha ketoglutarate cancer genetics chemical bond cofactor demethylation design disease diagnosis electronic structure enzyme substrate complex epigenetic drug epigenetic regulation experience flexibility geometric structure histone demethylase inhibitor/antagonist insight interdisciplinary approach knowledge base larynx Carcinoma malignant breast neoplasm novel preference tool undergraduate student

项目摘要

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.

项目概要表观遗传调控最重要的工具之一是组蛋白的去甲基化最丰富的组蛋白去甲基酶属于非血红素铁和2-氧化戊二酸-。 (2OG) 依赖的 JmjC- 亚家族，催化 Nε-甲基赖氨酸残基的去甲基化 KDM4A 和 KDM7B 是 Fe (II) 和 2OG 依赖性组蛋白赖氨酸脱甲基酶。与多种癌症有关，如前列腺癌、乳腺癌、喉癌、胃癌和子宫内膜癌。当前的提议将多尺度计算方法与先进的光谱相结合阐明两者之间原子和电子结构水平差异的技术非血红素 Fe (II) 和 2-酮戊二酸 (2OG) 依赖性组蛋白去甲基酶 (KDM)：KDM4A 和 KDM7B 涉及：i) 共底物 - 2OG、H3 组蛋白和双氧的结合；结合位点、第二球体和更远距离之间的长程相关运动我们知识中的这一空白对于结合过程至关重要。基数不能通过孤立的实验或计算方法来解决。拟议的研究将揭示 KDM4A 对三重的偏好的原子方面甲基化赖氨酸残基和 KDM7B 对二甲基化和单甲基化赖氨酸的研究。将阐明为什么 KDM4A 能够结合精氨酸残基并使其去甲基化，而与 KDM7B。这项研究将缩小关于蛋白质环境如何在两个 KDM 在完整催化的形成过程中选择性地稳定重要物质该研究还将确定特定的长程酶-底物复合物。关键结合残基与第二球残基和更远距离的相关运动这种相关的相互作用预计是酶选择性的。为酶选择性表观遗传药物的设计提供了新的机会。该研究计划的一个方面是它将为有积极性的本科生提供独特的有机会利用现代计算和实验进行顶级研究方法符合学术研究增强奖的使命。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From random to rational: improving enzyme design through electric fields, second coordination sphere interactions, and conformational dynamics.

从随机到理性：通过电场、第二配位球相互作用和构象动力学改进酶设计。

DOI：
发表时间：
2023-10-18
期刊：
影响因子：
8.4
作者：
Chaturvedi, Shobhit S;Bím, Daniel;Christov, Christo Z;Alexandrova, Anastassia N
通讯作者：
Alexandrova, Anastassia N

Dioxygen Binding Is Controlled by the Protein Environment in Non-heme FeII and 2-Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene-Forming Enzyme.

双氧结合受非血红素 FeII 和 2-氧化戊二酸加氧酶中蛋白质环境的控制：组蛋白脱甲基酶 PHF8 和乙烯形成酶的研究。

DOI：
发表时间：
2023-04-25
期刊：
影响因子：
0
作者：
Chaturvedi, Shobhit S;Thomas, Midhun George;Rifayee, Simahudeen Bathir Jaber Sathik;White, Walter;Wildey, Jon;Warner, Cait;Schofield, Christopher J;Hu, Jian;Hausinger, Robert P;Karabencheva;Christov, Christo Z
通讯作者：
Christov, Christo Z

YfeX - A New Platform for Carbene Transferase Development with High Intrinsic Reactivity.

YfeX - 具有高内在反应性的卡宾转移酶开发新平台。

DOI：
发表时间：
2022-11-21
期刊：
影响因子：
0
作者：
Sosa Alfaro, Victor;Waheed, Sodiq O;Palomino, Hannah;Knorrscheidt, Anja;Weissenborn, Martin;Christov, Christo Z;Lehnert, Nicolai
通讯作者：
Lehnert, Nicolai

Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.

KDM6 组蛋白去甲基酶的催化 - 非血红素铁 (II) 中心、第二配位球和长程相互作用之间的协同作用。

DOI：
发表时间：
2023-09-12
期刊：
影响因子：
0
作者：
Rifayee, Simahudeen Bathir Jaber Sathik;Chaturvedi, Shobhit S;Warner, Cait;Wildey, Jon;White, Walter;Thompson, Martin;Schofield, Christopher J;Christov, Christo Z
通讯作者：
Christov, Christo Z

What Is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

酶促组蛋白 N-甲基精氨酸去甲基化的催化机制是什么？它会受到外部电场的影响吗？