Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.
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 in...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2007
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| _version_ | 1826272840000733184 |
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| author | Ng, S Kavanagh, K McDonough, M Butler, D Pilka, E Lienard, B Bray, J Savitsky, P Gileadi, O von Delft, F Rose, N Offer, J Scheinost, J Borowski, T Sundstrom, M Schofield, C Oppermann, U |
| author_facet | Ng, S Kavanagh, K McDonough, M Butler, D Pilka, E Lienard, B Bray, J Savitsky, P Gileadi, O von Delft, F Rose, N Offer, J Scheinost, J Borowski, T Sundstrom, M Schofield, C Oppermann, U |
| author_sort | Ng, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:18:56Z |
| format | Journal article |
| id | oxford-uuid:545da9d0-2eec-44f0-b3e8-fdd00c4f13cd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:18:56Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:545da9d0-2eec-44f0-b3e8-fdd00c4f13cd2022-03-26T16:37:25ZCrystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:545da9d0-2eec-44f0-b3e8-fdd00c4f13cdEnglishSymplectic Elements at Oxford2007Ng, SKavanagh, KMcDonough, MButler, DPilka, ELienard, BBray, JSavitsky, PGileadi, Ovon Delft, FRose, NOffer, JScheinost, JBorowski, TSundstrom, MSchofield, COppermann, UPost-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. |
| spellingShingle | Ng, S Kavanagh, K McDonough, M Butler, D Pilka, E Lienard, B Bray, J Savitsky, P Gileadi, O von Delft, F Rose, N Offer, J Scheinost, J Borowski, T Sundstrom, M Schofield, C Oppermann, U Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title | Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title_full | Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title_fullStr | Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title_full_unstemmed | Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title_short | Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. |
| title_sort | crystal structures of histone demethylase jmjd2a reveal basis for substrate specificity |
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