The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an 
essential role in early development and hematopoiesis. The biological function 
of MLL1 is mediated by the histone H3K4 methyltransferase activity of the 
carboxyl-terminal SET domain. We have determined the crystal structure of the 
MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 
peptide. This structure indicates that, in order to form a well-ordered active 
site, a highly variable but essential component of the SET domain must be 
repositioned. To test this idea, we compared the effect of the addition of MLL 
complex members on methyltransferase activity and show that both RbBP5 and Ash2L 
but not Wdr5 stimulate activity. Additionally, we have determined the effect of 
posttranslational modifications on histone H3 residues downstream and upstream 
from the target lysine and provide a structural explanation for why H3T3 
phosphorylation and H3K9 acetylation regulate activity.