Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives

作者：Niwa Hideaki; Handa Noriko; Tomabechi Yuri; Honda Keiko; Toyama Mitsutoshi; Ohsawa Noboru; Shirouzu Mikako; Kagechika Hiroyuki; Hirano Tomoya; Umehara Takashi; Yokoyama Shigeyuki^*

来源：Acta Crystallographica Section D-Biological Crystallography, 2013, 69(4): 595-602.

DOI：10.1107/S0907444912052092

• chromatin
• epigenetics
• methylases
• nucleosome

SET7/9 is a protein lysine methyltransferase that methylates histone H3 and nonhistone proteins such as p53, TAF10 and oestrogen receptor . 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 substratepeptide 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.

• 出版日期2013-4