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Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9—AdoMet
Author(s) -
Kwon Taewoo,
Chang Jeong Ho,
Kwak Eunyee,
Lee Chang Wook,
Joachimiak Andrzej,
Kim Young Chang,
Lee Jae Woon,
Cho Yunje
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg025
Subject(s) - national laboratory , biology , library science , research center , physics , political science , engineering physics , computer science , law
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 Å 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.