Methylation of lysine residues in the N-terminal tails of histones is thought to 
represent an important component of the mechanism that regulates chromatin 
structure. The evolutionarily conserved SET domain occurs in most proteins known 
to possess histone lysine methyltransferase activity. We present here the 
crystal structure of a large fragment of human SET7/9 that contains a N-terminal 
beta-sheet domain as well as the conserved SET domain. Mutagenesis identifies 
two residues in the C terminus of the protein that appear essential for 
catalytic activity toward lysine-4 of histone H3. Furthermore, we show how the 
cofactor AdoMet binds to this domain and present biochemical data supporting the 
role of invariant residues in catalysis, binding of AdoMet, and interactions 
with the peptide substrate.