Abstract
The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Enzyme Inhibitors / pharmacology*
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Humans
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Inhibitory Concentration 50
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
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Jumonji Domain-Containing Histone Demethylases / chemistry
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Models, Molecular
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Plant Growth Regulators / pharmacology*
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Protein Conformation
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Substrate Specificity
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Succinates / pharmacology*
Substances
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Enzyme Inhibitors
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Plant Growth Regulators
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Succinates
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Jumonji Domain-Containing Histone Demethylases
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daminozide
Associated data
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PDB/4AI8
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PDB/4AI9
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PDB/4DO0