The SET domain contains the catalytic center of lysine methyltransferases that 
target the N-terminal tails of histones and regulate chromatin function. Here we 
report the structure of the SET7/9 protein in the absence and presence of its 
cofactor product, S-adenosyl-L-homocysteine (AdoHcy). A knot within the SET 
domain helps form the methyltransferase active site, where AdoHcy binds and 
lysine methylation is likely to occur. A structure-guided comparison of 
sequences within the SET protein family suggests that the knot substructure and 
active site environment are conserved features of the SET domain.