Browse by author
Lookup NU author(s): Dr Roman Belle, Dr Vinod Kumar, Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Nε-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, Nε-trimethyllysine, is specifically recognised by Nε-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 Nε-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (KPme3), by Nε-trimethyllysine histone binding proteins and Nε-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3KP4me3 binds more tightly than the natural H3K4me3 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.
Author(s): Belle R, Kamps JJAG, Poater J, Kumar K, Pieters BJGE, Salah E, Claridge TDW, Paton RS, Bickelhaupt FM, Kawamura A, Schofield CJ, Mecinovic J
Publication type: Article
Publication status: Published
Journal: Communications Chemistry
Year: 2022
Volume: 5
Online publication date: 07/03/2022
Acceptance date: 03/02/2022
Date deposited: 09/03/2022
ISSN (electronic): 2399-3669
Publisher: Springer Nature
URL: https://doi.org/10.1038/s42004-022-00640-4
DOI: 10.1038/s42004-022-00640-4
Altmetrics provided by Altmetric
