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

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
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-06-01 至 2024-05-31

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英文摘要
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.
期刊论文(7)
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会议论文
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
影响因子: --
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)
影响因子: --
作者: [Rifayee,SimahudeenBathirJaberSathik, Chaturvedi,ShobhitS, Warner,Cait, Wildey,Jon, White,Walter, Thompson,Martin, Schofield,ChristopherJ, Christov,ChristoZ]
通讯作者: Christov,ChristoZ
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
国内基金
海外基金
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 项目类别:
    面上项目
  • 资助金额:
    55.0万元
  • 批准年份:
    2019
  • 负责人:
    辛贵忠
  • 依托单位: