The Cation−π Interaction at Protein–Protein Interaction Interfaces: Developing and Learning from Synthetic Mimics of Proteins That Bind Methylated Lysines

• DOI: 10.1021/ar300072g
• Publication Date: 2012-06-22T19:10:26Z
• Authors: Kevin D. Daze; Fraser Hof
• Keywords: Demethylase

First discovered over 60 years ago, post-translational methylation was considered an irreversible modification until the initial discoveries of demethylase enzymes in 2004. Now researchers understand that this process serves as a dynamic and complex control mechanism is misregulated numerous diseases. Lysine most often found on histone proteins can effect gene regulation, epigenetic inheritance, cancer. Because connection to disease, many responsible for are targets new cancer therapies. Although our understanding biology has advanced at astonishing rate within last 5 years, chemical approaches studying disrupting these pathways only now gaining momentum.In general, methylate lysine arginine residues with very high specificity both location state. Each methylated target focused hot spot inducible protein–protein interaction (PPI). Conceptually, or subtle leads no change charge small changes size, but it significantly alters hydration energies hydrogen bonding potential side chains. Nature evolved special motif recognizing states lysine, called "aromatic cage", collection aromatic protein residues, accompanied by one more neighboring anionic residues. The combination favorable cation−π, electrostatic, van der Waals interactions, well size matching, gives degree state.This Account summarizes development various supramolecular host system scaffolds developed recognize bind ammonium cations, such trimethyllysine, basis their Early systems bound pure, buffered water failed achieve biochemically relevant affinities selectivities. Surprisingly, use simple well-known p-sulfonatocalix[4]arene provides protein-like selectivities trimethyllysine water. New analogs, created synthetic same scaffold, allow further tuning trimethyllysine. Our studies each family hosts paint consistent picture: cation−π interactions electrostatics important, solvation effects complex. Rigidity especially important host–guest function pure Despite simplicity, take lessons into account rival surpass those naturally counterparts. stage set next act: compounds tunable adaptable tools modern biology.