A survey of the human genome was performed to understand the constituency of 
protein methyltransferases (both protein arginine and lysine methyltransferases) 
and the relatedness of their catalytic domains. We identified 51 protein lysine 
methyltransferase proteins based on similarity to the canonical Drosophila 
Su(var)3-9, enhancer of zeste (E(z)), and trithorax (trx) domain. Disruptor of 
telomeric silencing-1-like, a known protein lysine methyltransferase, did not 
fit within the protein lysine methyltransferase family, but did group with the 
protein arginine methyltransferases, along with 44 other proteins, including the 
METTL and NOP2/Sun domain family proteins. We show that a representative METTL, 
METTL11A, demonstrates catalytic activity as a histone methyltransferase. We 
also solved the co-crystal structures of disruptor of telomeric silencing-1-like 
with S-adenosylmethionine and S-adenosylhomocysteine bound in its active site. 
The conformation of both ligands is virtually identical to that found in known 
protein arginine methyltransferases, METTL and NOP2/Sun domain family proteins 
and is distinct from that seen in the Drosophila Su(var)3-9, enhancer of zeste 
(E(z)), and trithorax (trx) domain protein lysine methyltransferases. We have 
developed biochemical assays for 11 members of the protein methyltransferase 
target class and have profiled the affinity of three ligands for these enzymes: 
the common methyl-donating substrate S-adenosylmethionine; the common reaction 
product S-adenosylhomocysteine; and the natural product sinefungin. The affinity 
of each of these ligands is mapped onto the family trees of the protein lysine 
methyltransferases and protein arginine methyltransferases to reveal patterns of 
ligand recognition by these enzymes.