title: Druggability of methyl-lysine binding sites.
abstract: Structural modules that specifically recognize--or read--methylated or acetylated lysine residues on histone peptides are important components of chromatin-mediated signaling and epigenetic regulation of gene expression. Deregulation of epigenetic mechanisms is associated with disease conditions, and antagonists of acetyl-lysine binding bromodomains are efficacious in animal models of cancer and inflammation, but little is known regarding the druggability of methyl-lysine binding modules. We conducted a systematic structural analysis of readers of methyl marks and derived a predictive druggability landscape of methyl-lysine binding modules. We show that these target classes are generally less druggable than bromodomains, but that some proteins stand as notable exceptions.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Santiago
authors.forename: K
authors.initials: K
authors.lastname: Nguyen
authors.forename: M
authors.initials: M
authors.lastname: Schapira
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006657:Histones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D006657:Histones; D054852:Small Molecule Libraries; D008239:Lysine