title: Strategy to target the substrate binding site of SET domain protein methyltransferases.
abstract: Protein methyltransferases (PMTs) are a novel gene family of therapeutic relevance involved in chromatin-mediated signaling and other biological mechanisms. Most PMTs are organized around the structurally conserved SET domain that catalyzes the methylation of a substrate lysine. A few potent chemical inhibitors compete with the protein substrate, and all are anchored in the channel recruiting the methyl-accepting lysine. We propose a novel strategy to design focused chemical libraries targeting the substrate binding site, where a limited number of warheads each occupying the lysine-channel of multiple enzymes would be decorated by different substituents. A variety of sequence and structure-based approaches used to analyze the diversity of the lysine channel of SET domain PMTs support the relevance of this strategy. We show that chemical fragments derived from published inhibitors are valid warheads that can be used in the design of novel focused libraries targeting other PMTs.
authors: Structural Genomics Consortium, University of Toronto , MaRS Centre, South Tower, seventh floor, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.
authors: Kong T
authors: KT
authors: Nguyen
authors: Fengling
authors: F
authors: Li
authors: Gennadiy
authors: G
authors: Poda
authors: David
authors: D
authors: Smil
authors: Masoud
authors: M
authors: Vedadi
authors: Matthieu
authors: M
authors: Schapira
mesh_terms: D000596:Amino Acids / Q000032:analysis; D002843:Chromatin / Q000502:physiology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D007473:Ion Channels / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D010802:Phylogeny; D011485:Protein Binding; D011487:Protein Conformation; D011496:Protein Methyltransferases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D002843:Chromatin; D007473:Ion Channels; D054852:Small Molecule Libraries; D011496:Protein Methyltransferases; D008239:Lysine