Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.
Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combin...
| Glavni autori: | , , , , , , , , , , |
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
2010
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| Teme: |
| _version_ | 1826306422170714112 |
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| author | Rose, N Woon, E Kingham, G King, O Mecinović, J Clifton, I Ng, S Talib-Hardy, J Oppermann, U McDonough, M Schofield, C |
| author_facet | Rose, N Woon, E Kingham, G King, O Mecinović, J Clifton, I Ng, S Talib-Hardy, J Oppermann, U McDonough, M Schofield, C |
| author_sort | Rose, N |
| collection | OXFORD |
| description | Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds. |
| first_indexed | 2024-03-07T06:47:44Z |
| format | Journal article |
| id | oxford-uuid:fb6ea5e3-b920-4a8f-9659-f88a8a31c70f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:47:44Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:fb6ea5e3-b920-4a8f-9659-f88a8a31c70f2022-03-27T13:13:49ZSelective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fb6ea5e3-b920-4a8f-9659-f88a8a31c70fBinding, CompetitiveSpectrometry, Mass, Electrospray IonizationBinding Sitesanalogs and derivativeschemistryTyrosineStructure-Activity RelationshipCrystallography, X-Raychemical synthesisModels, MolecularCombinatorial Chemistry TechniquesOxalic Acidsantagonists and inhibitorsJumonji Domain-Containing Histone DemethylasesSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationEnglishStructural Genomics Consortium2010Rose, NWoon, EKingham, GKing, OMecinović, JClifton, INg, STalib-Hardy, JOppermann, UMcDonough, MSchofield, CFerrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds. |
| spellingShingle | Binding, Competitive Spectrometry, Mass, Electrospray Ionization Binding Sites analogs and derivatives chemistry Tyrosine Structure-Activity Relationship Crystallography, X-Ray chemical synthesis Models, Molecular Combinatorial Chemistry Techniques Oxalic Acids antagonists and inhibitors Jumonji Domain-Containing Histone Demethylases Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Rose, N Woon, E Kingham, G King, O Mecinović, J Clifton, I Ng, S Talib-Hardy, J Oppermann, U McDonough, M Schofield, C Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title | Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title_full | Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title_fullStr | Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title_full_unstemmed | Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title_short | Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. |
| title_sort | selective inhibitors of the jmjd2 histone demethylases combined nondenaturing mass spectrometric screening and crystallographic approaches |
| topic | Binding, Competitive Spectrometry, Mass, Electrospray Ionization Binding Sites analogs and derivatives chemistry Tyrosine Structure-Activity Relationship Crystallography, X-Ray chemical synthesis Models, Molecular Combinatorial Chemistry Techniques Oxalic Acids antagonists and inhibitors Jumonji Domain-Containing Histone Demethylases Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization |
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