title: Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives.
abstract: SET7/9 is a protein lysine methyltransferase that methylates histone H3 and nonhistone proteins such as p53, TAF10 and oestrogen receptor α. In previous work, novel inhibitors of SET7/9 that are amine analogues of the coenzyme S-(5'-adenosyl)-L-methionine (AdoMet) have been developed. Here, crystal structures of SET7/9 are reported in complexes with two AdoMet analogues, designated DAAM-3 and AAM-1, in which an n-hexylaminoethyl group or an n-hexyl group is attached to the N atom that replaces the S atom of AdoMet, respectively. In both structures, the inhibitors bind to the coenzyme-binding site and their additional alkyl chain binds in the lysine-access channel. The N atom in the azaalkyl chain of DAAM-3 is located at almost the same position as the N-methyl C atom of the methylated lysine side chain in the substrate-peptide complex structures and stabilizes complex formation by hydrogen bonding to the substrate-binding site residues of SET7/9. On the other hand, the alkyl chain of AAM-1, which is a weaker inhibitor than DAAM-3, binds in the lysine-access channel only through hydrophobic and van der Waals interactions. Unexpectedly, the substrate-binding site of SET7/9 complexed with AAM-1 specifically interacts with the artificial N-terminal sequence of an adjacent symmetry-related molecule, presumably stabilizing the alkyl chain of AAM-1.
authors.affiliation: RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Niwa
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tomabechi
authors.forename: Keiko
authors.initials: K
authors.lastname: Honda
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Toyama
authors.forename: Noboru
authors.initials: N
authors.lastname: Ohsawa
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirano
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D018360:Crystallography, X-Ray; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D046911:Macromolecular Substances / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012436:S-Adenosylmethionine / Q000737:chemistry* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D012436:S-Adenosylmethionine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human
keywords: chromatin; epigenetics; methylases; nucleosome