title: Structural biology of human H3K9 methyltransferases.
abstract: SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity.
  
  
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authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Lunin
authors.forename: Tatiana
authors.initials: T
authors.lastname: Antoshenko
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Valérie
authors.initials: V
authors.lastname: Campagna-Slater
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
mesh_terms: D020134:Catalytic Domain; D003460:Crystallization; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase