Methylation of lysine residues of histones is an important epigenetic mark that 
correlates with functionally distinct regions of chromatin. We present here the 
crystal structure of a ternary complex of the enzyme Pr-Set7 (also known as 
Set8) that methylates Lys 20 of histone H4 (H4-K20). We show that the enzyme is 
exclusively a mono-methylase and is therefore responsible for a signaling role 
quite distinct from that established by other enzymes that target this histone 
residue. We provide evidence from NMR for the C-flanking domains of SET proteins 
becoming ordered upon addition of AdoMet cofactor and develop a model for the 
catalytic cycle of these enzymes. The crystal structure reveals the basis of the 
specificity of the enzyme for H4-K20 because a histidine residue within the 
substrate, close to the target lysine, is required for completion of the active 
site. We also show how a highly variable component of the SET domain is 
responsible for many of the enzymes' interactions with its target histone 
peptide and probably also how this part of the structure ensures that Pr-Set7 is 
nucleosome specific.