title: Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet.
abstract: The methylation of lysine residues of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Here, we report two crystal structures of SET7/9, a histone methyltransferase (HMTase) that transfers methyl groups to Lys4 of histone H3, in complex with S-adenosyl-L-methionine (AdoMet) determined at 1.7 and 2.3 A resolution. The structures reveal an active site consisting of: (i) a binding pocket between the SET domain and a c-SET helix where an AdoMet molecule in an unusual conformation binds; (ii) a narrow substrate-specific channel that only unmethylated lysine residues can access; and (iii) a catalytic tyrosine residue. The methyl group of AdoMet is directed to the narrow channel where a substrate lysine enters from the opposite side. We demonstrate that SET7/9 can transfer two but not three methyl groups to unmodified Lys4 of H3 without substrate dissociation. The unusual features of the SET domain-containing HMTase discriminate between the un- and methylated lysine substrate, and the methylation sites for the histone H3 tail.
authors.affiliation: National Creative Research Initiative Center for Structural Biology and Department of Life Science, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, KyungBook 790-784, South Korea.
authors.forename: Taewoo
authors.initials: T
authors.lastname: Kwon
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Chang
authors.forename: Eunyee
authors.initials: E
authors.lastname: Kwak
authors.forename: Chang Wook
authors.initials: CW
authors.lastname: Lee
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Young Chang
authors.initials: YC
authors.lastname: Kim
authors.forename: Jaewoon
authors.initials: J
authors.lastname: Lee
authors.forename: Yunje
authors.initials: Y
authors.lastname: Cho
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011496:Protein Methyltransferases; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D006657:Histones; D012097:Repressor Proteins; D012436:S-Adenosylmethionine; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine