Journal
COMMUNICATIONS CHEMISTRY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42004-022-00640-4
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Funding
- European Research Council (ERC) [ChemEpigen-715691]
- Cancer Research UK [C8717/A18245, C8717/A28285]
- EPSRC [EP/M50659X/1, EP/L003376/1, EP/L015838/1J]
- Clarendon Scholarship
- Netherlands Organization for Scientific Research (NWO-ALW)
- Netherlands Organization for Scientific Research (NWO-CW)
- Netherlands Organization for Scientific Research (NWO-EW)
- Spanish MINECO [PID2019-106830GB-I00, MDM-2017-0767]
- World Bank Education Grant
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The substitution of nitrogen with phosphorus substantially affects the interactions between N-epsilon-methyllysine binding proteins and demethylases.
N-epsilon-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The 'highest' methylation mark, N-epsilon-trimethyllysine, is specifically recognised by N-epsilon-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 N-epsilon-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (K(P)me(3)), by N-epsilon-trimethyllysine histone binding proteins and N-epsilon-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3K(P)4me(3) binds more tightly than the natural H3K4me(3) 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, e.g. 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. N-epsilon-methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription, and understanding the extent to which histone N(epsilon-)methyllysine readers and erasers can manifest selectivity is of fundamental and medicinal interest. Here, the authors study the phosphonium analogue of N-epsilon-trimethyllysine, finding that a subtle substitution from nitrogen to phosphorus substantially affects its interactions with N-epsilon-methyllysine readers and erasers.
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