2os2

File:2os2.gif

spinqualitylabelsall models 2os2, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of JMJD2A complexed with histone H3 peptide trimethylated at Lys36

OverviewOverview

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.

About this StructureAbout this Structure

2OS2 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity., Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BM, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer J, Scheinost JC, Borowski T, Sundstrom M, Schofield CJ, Oppermann U, Nature. 2007 Jul 5;448(7149):87-91. Epub 2007 Jun 24. PMID:17589501

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