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The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(ϵ)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.

Original publication

DOI

10.1074/jbc.m114.555052

Type

Journal article

Journal

The Journal of Biological Chemistry

Publication Date

06/2014

Volume

289

Pages

18302 - 18313

Addresses

From the Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom.

Keywords

Humans, Lysine, Nuclear Proteins, Histones, Minor Histocompatibility Antigens, Crystallography, X-Ray, Sequence Alignment, Species Specificity, Amino Acid Sequence, Protein Structure, Tertiary, Methylation, Models, Molecular, Molecular Sequence Data, Male