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

• 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
• 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

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 蛋白质。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 组蛋白。 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；和 ii) 结合位点、第二球体和更远距离之间的长程相关运动 对于结合过程至关重要的蛋白质区域。我们的知识差距 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 甲基化的赖氨酸残基和 KDM7B 的二甲基化和单甲基化赖氨酸。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如何改变两者的蛋白质环境的知识差距 KDM 在完整催化的形成过程中选择性地稳定重要物质 高效的酶-底物复合物。该研究还将确定具体的长期 关键结合残基与第二球残基和更远距离的相关运动 蛋白质区域。这种相关的相互作用预计是酶选择性的，这将 为酶选择性表观遗传药物的设计提供了新的机会。令人兴奋的 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

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

非血红素 Fe II 和 2-氧化戊二酸加氧酶中的双氧结合受蛋白质环境控制：组蛋白脱甲基酶 PHF8 和乙烯形成酶的研究

• DOI: 10.1002/chem.202300138
• 发表时间: 2023
• 期刊: Chemistry – A European Journal
• 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‐Christova, Tatayana G.
• 通讯作者: Karabencheva‐Christova, Tatayana G.

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: 10.1002/chem.202301305
• 发表时间: 2023
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Rifayee,SimahudeenBathirJaberSathik;Chaturvedi,ShobhitS;Warner,Cait;Wildey,Jon;White,Walter;Thompson,Martin;Schofield,ChristopherJ;Christov,ChristoZ
• 通讯作者: Christov,ChristoZ

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

• DOI: 10.1002/chem.202201474
• 发表时间: 2022-11-21
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Alfaro, Victor Sosa;Waheed, Sodiq O.;Palomino, Hannah;Knorrscheidt, Anja;Weissenborn, Martin;Christov, Christo Z.;Lehnert, Nicolai
• 通讯作者: Lehnert, Nicolai

Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?

第二个配位球体和远距离相互作用是否可以调节非血红素Fe（II）依赖性组蛋白脱甲基酶中的氢原子转移？

• DOI: 10.1021/jacsau.2c00345
• 发表时间: 2022-09-26
• 期刊: JACS AU
• 影响因子: 8
• 作者: Chaturvedi, Shobhit S;Jaber Sathik Rifayee, Simahudeen Bathir;Waheed, Sodiq O;Wildey, Jon;Warner, Cait;Schofield, Christopher J;Karabencheva-Christova, Tatyana G;Christov, Christo Z
• 通讯作者: Christov, Christo Z