Binding Methylarginines and Methyllysines as Free Amino Acids: A Comparative Study of Multiple Host Classes.

Methylated free amino acids are an important class of targets for host-guest chemistry that have recognition properties distinct from those of methylated peptides and proteins. We present comparative binding studies for three different host classes that are each studied with multiple methylated arginines and lysines to determine fundamental structure-function relationships. The hosts studied are all anionic and include three calixarenes, two acyclic cucurbiturils, and two other cleft-like hosts, a clip and a tweezer. We determined the binding association constants for a panel of methylated amino acids using indicator displacement assays. The acyclic cucurbiturils display stronger binding to the methylated amino acids, and some unique patterns of selectivity. The two other cleft-like hosts follow two different trends, shallow host (clip) following similar trends to the calixarenes, and the other more closed host (tweezer) binding certain less-methylated amino acids stronger than their methylated counterparts. Molecular modelling sheds some light on the different preferences of the various hosts. The results identify hosts with new selectivities and with affinities in a range that could be useful for biomedical applications. The overall selectivity patterns are explained by a common framework that considers the geometry, depth of binding pockets, and functional group participation across all host classes.

Structural aspects of small-molecule inhibition of methyllysine reader proteins.

Methyl reader proteins recognize and bind to post-translationally methylated residues. They execute the commands issued by protein methyltransferases and play functional roles in diverse cellular processes including gene regulation, development and oncogenesis. Efforts to inhibit these proteins are relatively new. Only a small number of methyl reader proteins belonging to the chromodomain, malignant brain tumor domain, plant homeodomain finger and Tudor domain families have been targeted by chemical inhibitors. This review summarizes inhibitors that have been reported to date, and provides a perspective for future progress. Structural determinants for methyl reader inhibition will be presented, along with an analysis of the molecular interactions that control potency and selectivity for inhibitors of each family.