4qxc

Crystal structure of histone demethylase KDM2A-H3K36ME2 with NOG

spinqualitylabelsall models 4qxc, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qxc is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NI, OGA NonStd Res: MLY Related: 4tn7, 2yu1, 2yu2, 4qx7, 4qx8, 4qxb, 4qxh, 4qwn Activity: [Histone_H3-lysine-36_demethylase [Histone H3]-lysine-36 demethylase], with EC number 1.14.11.27 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The dynamic reversible methylation of lysine residues on histone proteins is central to chromatin biology. Key components are demethylase enzymes, which remove methyl moieties from lysine residues. KDM2A, a member of the Jumonji C domain-containing histone lysine demethylase family, specifically targets lower methylation states of H3K36. Here, structural studies reveal that H3K36 specificity for KDM2A is mediated by the U-shaped threading of the H3K36 peptide through a catalytic groove within KDM2A. The side chain of methylated K36 inserts into the catalytic pocket occupied by Ni(2+) and cofactor, where it is positioned and oriented for demethylation. Key residues contributing to K36me specificity on histone H3 are G33 and G34 (positioned within a narrow channel), P38 (a turn residue), and Y41 (inserts into its own pocket). Given that KDM2A was found to also bind the H3K36me3 peptide, we postulate that steric constraints could prevent alpha-ketoglutarate from undergoing an "off-line"-to-"in-line" transition necessary for the demethylation reaction. Furthermore, structure-guided substitutions of residues in the KDM2A catalytic pocket abrogate KDM2A-mediated functions important for suppression of cancer cell phenotypes. Together, our results deduce insights into the molecular basis underlying KDM2A regulation of the biologically important methylated H3K36 mark. A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36.,Cheng Z, Cheung P, Kuo AJ, Yukl ET, Wilmot CM, Gozani O, Patel DJ Genes Dev. 2014 Aug 15;28(16):1758-71. doi: 10.1101/gad.246561.114. PMID:25128496 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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