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- Title
Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.
- Authors
Ng, Stanley S; Kavanagh, Kathryn L; McDonough, Michael A; Butler, Danica; Pilka, Ewa S; Lienard, Benoit M R; Bray, James E; Savitsky, Pavel; Gileadi, Opher; von Delft, Frank; Rose, Nathan R; Offer, John; Scheinost, Johanna C; Borowski, Tomasz; Sundstrom, Michael; Schofield, Christopher J; Oppermann, Udo
- Abstract
Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a 'histone code' in epigenetic regulation. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation. The discovery of lysyl demethylases using flavin (amine oxidases) or Fe(II) and 2-oxoglutarate as cofactors (2OG oxygenases) has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.
- Publication
Nature, 2007, Vol 448, Issue 7149, p87
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature05971