Hideaki Niwa, Noriko Handa, Yuri Tomabechi, Keiko Honda, Mitsutoshi Toyama, Noboru Ohsawa, Mikako Shirouzu, Hiroyuki Kagechika, Tomoya Hirano, Takashi Umehara, Shigeyuki Yokoyama
RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama, Japan.
Acta crystallographica. Section D, Biological crystallography 2013 AprSET7/9 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.
Hideaki Niwa, Noriko Handa, Yuri Tomabechi, Keiko Honda, Mitsutoshi Toyama, Noboru Ohsawa, Mikako Shirouzu, Hiroyuki Kagechika, Tomoya Hirano, Takashi Umehara, Shigeyuki Yokoyama. Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives. Acta crystallographica. Section D, Biological crystallography. 2013 Apr;69(Pt 4):595-602
PMID: 23519668
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