Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins

Abstract

A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation–π interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain. These results have implications in rational drug design by specifically targeting the aromatic cage of readers of trimethyllysine.

Cation–π Interactions Contribute to Substrate Recognition in γ‐Butyrobetaine Hydroxylase Catalysis

“…Cation–π interactions are involved in associations of Cys‐loop receptors and G‐protein‐coupled receptors with neurotransmitters, including acetylcholine, serotonin, dopamine, epinephrine, and histamine . Studies on chromatin interactions involved in the regulation of gene expression reveal that “reader domain” proteins that recognize trimethyllysine‐containing histone tails interact through cation–π interactions . Thus, along with hydrophobic effects, hydrogen bonding, ion pairing, and van der Waals interactions, cation–π interactions are crucial noncovalent forces in protein–protein and protein–ligand associations …”

Host–guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents

“…. 20 Increased host rigidity was needed, and so we turned to the use of macrocyclic host molecules. a little bit closer'' -Tegan and Sara A comparison to reader proteins was helpful in moving the program forward.…”

“…15a). 20,21 The physicochemical properties of methyllysines, described earlier, make them especially challenging targets for selective enrichment. Pan-specific reagents for phosphorylated peptides are the archetypal examples.…”

Chemical probes for methyl lysine reader domains

“…Kme binding sites are generally made up of an aromatic cage involving 3 to 4 aromatic amino acids, and often an acidic residue to hydrogen bond to the Kme cation in the case of mono- and dimethyllysine (Kme1,2) recognition, or simply to balance the charge in the case of Kme3 [27,28]. The Patel lab introduced a useful division of Kme readers into “cavity insertion” versus “surface groove” binders [29], and subsequent work toward chemical probes has been informed by this ontology and confirmed its relevance to ligand design.…”