SET domain methyltransferases deposit methyl marks on specific histone tail 
lysine residues and play a major role in epigenetic regulation of gene 
transcription. We solved the structures of the catalytic domains of GLP, G9a, 
Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in 
their apo conformation or in complex with the methyl donating cofactor, and 
peptide substrates. We analyzed the structural determinants for methylation 
state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show 
that the I-SET domain acts as a rigid docking platform, while induced-fit of the 
Post-SET domain is necessary to achieve a catalytically competent conformation. 
We also propose a model where long-range electrostatics bring enzyme and histone 
substrate together, while the presence of an arginine upstream of the target 
lysine is critical for binding and specificity.
ENHANCED VERSION: This article can also be viewed as an enhanced version in 
which the text of the article is integrated with interactive 3D representations 
and animated transitions. Please note that a web plugin is required to access 
this enhanced functionality. Instructions for the installation and use of the 
web plugin are available in Text S1.