title: Structural chemistry of the histone methyltransferases cofactor binding site.
abstract: Histone methyltransferases (HMTs) transfer a methyl group from the cofactor S-adenosyl methionine to lysine or arginine residues on histone tails, thereby regulating chromatin compaction, binding of effector proteins and gene transcription. HMTs constitute an emerging target class in diverse disease areas, and selective chemical probes are necessary for target validation. Potent and selective competitors of the substrate peptide have been reported, but the chemical tractability of the cofactor binding site is poorly understood. Here, a systematic analysis of this site across structures of 14 human HMTs or close homologues was conducted. The druggability, interaction hotspots, and diversity of the cofactor binding pocket were dissected. This analysis strongly suggests that this site is chemically tractable. General principles underlying tight binding and specific guidelines to achieve selective inhibition are presented.
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS Centre, Toronto, Ontario, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Campagna-Slater
authors.forename: Man Wai
authors.initials: MW
authors.lastname: Mok
authors.forename: Kong T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Rafael
authors.initials: R
authors.lastname: Najmanovich
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
mesh_terms: D001665:Binding Sites; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase