Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins
<i>N</i><sup>ε</sup>-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, <i>N</i><sup>ε</sup>-trimethyllysine, is specifically recognised by <i>N</i&...
| Main Authors: | , , , , , , , , , , , |
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| Formato: | Journal article |
| Idioma: | English |
| Publicado em: |
Springer Nature
2022
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| Assuntos: |
| _version_ | 1826311043127705600 |
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| author | Belle, R Kamps, JJAG Poater, J Kumar, K Pieters, BJGE Salah, E Claridge, TDW Paton, RS Matthias Bickelhaupt, F Kawamura, A Schofield, CJ Mecinović, J |
| author_facet | Belle, R Kamps, JJAG Poater, J Kumar, K Pieters, BJGE Salah, E Claridge, TDW Paton, RS Matthias Bickelhaupt, F Kawamura, A Schofield, CJ Mecinović, J |
| author_sort | Belle, R |
| collection | OXFORD |
| description | <i>N</i><sup>ε</sup>-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, <i>N</i><sup>ε</sup>-trimethyllysine, is specifically recognised by <i>N</i><sup>ε</sup>-trimethyllysine binding ‘reader’ domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies on the recognition of the closest positively charged <i>N</i><sup>ε</sup>-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (K<sub>P</sub>me<sub>3</sub>), by <i>N</i><sup>ε</sup>-trimethyllysine histone binding proteins and <i>N</i><sup>ε</sup>-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3K<sub>P</sub>4me<sub>3</sub> binds more tightly than the natural H3K4me<sub>3</sub> substrate, though the relative differences in binding affinity vary. Studies with JmjC demethylases show that some, but not all, of them can accept the phosphonium analogue of their natural substrates and that the methylation state selectivity can be changed by substitution of nitrogen for phosphorus. The combined results reveal that very subtle changes, <i>e.g.</i> substitution of nitrogen for phosphorus, can substantially affect interactions between ligand and reader domains / demethylases, knowledge that we hope will inspire the development of highly selective small molecules modulating their activity. |
| first_indexed | 2024-03-07T08:02:32Z |
| format | Journal article |
| id | oxford-uuid:b4cf7a40-4911-41bf-a2ce-0443d9a7b7d6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:02:32Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:b4cf7a40-4911-41bf-a2ce-0443d9a7b7d62023-10-06T11:43:02ZReading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteinsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b4cf7a40-4911-41bf-a2ce-0443d9a7b7d6Chemical toolsMethylationBiocatalysisEnglishSymplectic ElementsSpringer Nature2022Belle, RKamps, JJAGPoater, JKumar, KPieters, BJGESalah, EClaridge, TDWPaton, RSMatthias Bickelhaupt, FKawamura, ASchofield, CJMecinović, J<i>N</i><sup>ε</sup>-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, <i>N</i><sup>ε</sup>-trimethyllysine, is specifically recognised by <i>N</i><sup>ε</sup>-trimethyllysine binding ‘reader’ domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies on the recognition of the closest positively charged <i>N</i><sup>ε</sup>-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (K<sub>P</sub>me<sub>3</sub>), by <i>N</i><sup>ε</sup>-trimethyllysine histone binding proteins and <i>N</i><sup>ε</sup>-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3K<sub>P</sub>4me<sub>3</sub> binds more tightly than the natural H3K4me<sub>3</sub> substrate, though the relative differences in binding affinity vary. Studies with JmjC demethylases show that some, but not all, of them can accept the phosphonium analogue of their natural substrates and that the methylation state selectivity can be changed by substitution of nitrogen for phosphorus. The combined results reveal that very subtle changes, <i>e.g.</i> substitution of nitrogen for phosphorus, can substantially affect interactions between ligand and reader domains / demethylases, knowledge that we hope will inspire the development of highly selective small molecules modulating their activity. |
| spellingShingle | Chemical tools Methylation Biocatalysis Belle, R Kamps, JJAG Poater, J Kumar, K Pieters, BJGE Salah, E Claridge, TDW Paton, RS Matthias Bickelhaupt, F Kawamura, A Schofield, CJ Mecinović, J Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title | Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title_full | Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title_fullStr | Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title_full_unstemmed | Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title_short | Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| title_sort | reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins |
| topic | Chemical tools Methylation Biocatalysis |
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