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  • The EMBO Journal (2003) 22, 292 - 303
  • doi:10.1093/emboj/cdg025

Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9–AdoMet

Taewoo Kwon1,2, Jeong Ho Chang1,2, Eunyee Kwak2, Chang Wook Lee1,2, Andrzej Joachimiak3, Young Chang Kim3, Jae Woon Lee2 and Yunje Cho1,2

  1. National Creative Research Initiative Center for Structural Biology, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, KyungBook 790-784, South Korea
  2. Department of Life Science, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, KyungBook 790-784, South Korea
  3. Biosciences Division, Structural Biology Center, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA

Correspondence to:

Yunje Cho, E-mail: yunje@postech.ac.kr

Received 10 October 2002; Accepted 18 November 2002; Revised 18 November 2002

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.

  • Keywords:

    • compact form of AdoMet,
    • 9 histone methyltransferase,
    • post-SET helix,
    • SET7,
    • SET domain,
    • substrate-specific channel