Structure and catalytic mechanism of the human histone methyltransferase SET7/9

Acetylation(1,2), phosphorylation(3) and methylation(4) of the amino-terminal tails of histones are thought to be involved in the regulation of chromatin structure and function(5-7). With just one exception(8,9), the enzymes identified in the methylation of specific lysine residues on histones (histone methyltransferases) belong to the SET family(10). The high-resolution crystal structure of a ternary complex of human SET7/9 with a histone peptide and cofactor reveals that the peptide substrate and cofactor bind on opposite surfaces of the enzyme. The target lysine accesses the active site of the enzyme and the S-adenosyl-L-methionine (AdoMet) cofactor by inserting its side chain into a narrow channel that runs through the enzyme, connecting the two surfaces. Here we show from the structure and from solution studies that SET7/9, unlike most other SET proteins, is exclusively a mono-methylase. The structure indicates the molecular basis of the specificity of the enzyme for the histone target, and allows us to propose a model for the methylation reaction that accounts for the role of many of the residues that are invariant across the SET family.