The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain 
SET histone methyltransferases that are implicated in human cancer progression. 
Here we report an analysis of the crystal structure of the full length human 
SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl 
donor cofactor. The structure revealed an overall compact architecture in which 
the "split-SET" domain adopts a canonical SET domain fold and closely assembles 
with a Zn-binding MYND domain and a C-terminal superhelical 9 α-helical bundle 
similar to that observed for the mouse SMYD1 structure. Together, these 
structurally interlocked domains impose a highly confined binding pocket for 
histone substrates, suggesting a regulated mechanism for its enzymatic activity. 
Our mutational and biochemical analyses confirm regulatory roles of the unique 
structural elements both inside and outside the core SET domain and establish a 
previously undetected preference for trimethylation of H4K20.