Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5

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 N ε -methyl ly...

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Bibliographic Details
Published in:Scientific reports 2022-11, Vol.12 (1), p.20680-12, Article 20680
Main Authors: Islam, Md. Saiful, Markoulides, Marios, Chowdhury, Rasheduzzaman, Schofield, Christopher J.
Format: Article
Language:English
Subjects:
631/45
631/45/320
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Binding Sites
Cell proliferation
Circadian Rhythm
Circadian rhythms
Embryogenesis
Embryonic growth stage
Enantiomers
Female
Histones
Humanities and Social Sciences
Humans
Hydroxylase
Hydroxylation
Hypoxia
Iron
Ketoglutaric acid
Ketoglutaric Acids
Lysine
Mixed Function Oxygenases
multidisciplinary
Oxygenase
Oxygenases
Pregnancy
Proteins
Psychotherapy
Ribosomal protein S6
Science
Science (multidisciplinary)
Structural analysis
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Summary: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 N ε -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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-24154-0