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Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase.

SET8 (also known as PR-SET7) is a histone H4-Lys-20-specific methyltransferase that is implicated in cell-cycle-dependent transcriptional silencing and mitotic regulation in metazoans. Herein we report the crystal structure of human SET8 (hSET8) bound to a histone H4 peptide bearing Lys-20 and the product cofactor S-adenosylhomocysteine. Histone H4 intercalates in the substrate-binding cleft as an extended parallel beta-strand. Residues preceding Lys-20 in H4 engage in an extensive array of salt bridge, hydrogen bond, and van der Waals interactions with hSET8, while the C-terminal residues bind through predominantly hydrophobic interactions. Mutational analysis of both the substrate-binding cleft and histone H4 reveals that interactions with residues in the N and C termini of the H4 peptide are critical for conferring substrate specificity. Finally, analysis of the product specificity indicates that hSET8 is a monomethylase, consistent with its role in the maintenance of Lys-20 monomethylation during cell division.

Pubmed ID: 15933070


  • Couture JF
  • Collazo E
  • Brunzelle JS
  • Trievel RC


Genes & development

Publication Data

June 15, 2005

Associated Grants


Mesh Terms

  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Recombinant Proteins
  • S-Adenosylhomocysteine
  • Static Electricity
  • Substrate Specificity