Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.
Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.
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DOI：
10.1038/s41598-022-24154-0
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发表时间：
2022-11-30
影响因子：
4.6
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Islam, Md Saiful;Markoulides, Marios;Chowdhury, Rasheduzzaman;Schofield, Christopher J.
JmjC（Jumonji-C）domain-containing 5（JMJD 5）在植物和人类的昼夜节律调节中起重要作用，并参与胚胎发育和细胞增殖。JMJD 5是JmjC亚家族的2-酮戊二酸（2 OG）和Fe（II）依赖性加氧酶，其包括组蛋白Nε-甲基赖氨酸脱甲基酶（KDM）和催化稳定醇产物形成的羟化酶。据报道，JMJD 5具有KDM活性，但已显示在体外催化来自人含染色体凝聚结构域蛋白1（RCCD 1）和核糖体蛋白S6（RPS 6）的序列中精氨酸残基的C-3羟基化。我们报告了与2 OG类似物复合的人JMJD 5的晶体学分析，所述2 OG类似物包括广泛使用的低氧模拟物吡啶-2，4-二羧酸盐、癌代谢物2-羟基戊二酸盐的D-和L-对映体以及环状N-羟基酰亚胺。结果支持JMJD 5作为蛋白质羟化酶的分配，并揭示JMJD 5具有异常紧凑的2 OG结合口袋，适合用于开发选择性抑制剂。它们将有助于开发化学探针，以研究JMJD 5在昼夜节律和发育中的生理相关作用，并探索其作为药物化学靶点的潜力。
JmjC (Jumonji-C) domain-containing 5 (JMJD5) plays important roles in circadian regulation in plants and humans and is involved in embryonic development and cell proliferation. JMJD5 is a 2-oxoglutarate (2OG) and Fe(II) dependent oxygenase of the JmjC subfamily, which includes histone Nε-methyl lysine-demethylases (KDMs) and hydroxylases catalysing formation of stable alcohol products. JMJD5 is reported to have KDM activity, but has been shown to catalyse C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6) in vitro. We report crystallographic analyses of human JMJD5 complexed with 2OG analogues, including the widely used hypoxia mimic pyridine-2,4-dicarboxylate, both D- and L-enantiomers of the oncometabolite 2-hydroxyglutarate, and a cyclic N-hydroxyimide. The results support the assignment of JMJD5 as a protein hydroxylase and reveal JMJD5 has an unusually compact 2OG binding pocket suitable for exploitation in development of selective inhibitors. They will be useful in the development of chemical probes to investigate the physiologically relevant roles of JMJD5 in circadian rhythm and development and explore its potential as a medicinal chemistry target.
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影响因子：
8.4
作者：
Hopkinson RJ;Tumber A;Yapp C;Chowdhury R;Aik W;Che KH;Li XS;Kristensen JBL;King ONF;Chan MC;Yeoh KK;Choi H;Walport LJ;Thinnes CC;Bush JT;Lejeune C;Rydzik AM;Rose NR;Bagg EA;McDonough MA;Krojer T;Yue WW;Ng SS;Olsen L;Brennan PE;Oppermann U;Muller-Knapp S;Klose RJ;Ratcliffe PJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A
影响因子：
4.8
作者：
Elkins, JM;Hewitson, KS;Schofield, CJ
通讯作者：
Schofield, CJ
DOI：
10.1039/c8cc00387d
发表时间：
2018-03-28
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Abboud MI;McAllister TE;Leung IKH;Chowdhury R;Jorgensen C;Domene C;Mecinović J;Lippl K;Hancock RL;Hopkinson RJ;Kawamura A;Claridge TDW;Schofield CJ
通讯作者：
Schofield CJ
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
158.5
作者：
Chertow, Glenn M.;Pergola, Pablo E.;Eckardt, Kai-Uwe
通讯作者：
Eckardt, Kai-Uwe