The most notable feature of the catalytic structure is that the AdoHcy and the peptide substrate are located on opposite sides of the SET domain and that there is a narrow channel passing through the enzyme that connects the peptide and cofactor binding surfaces. The target lysine residue of the substrate (Lys 4) is inserted into this channel so that its amine can access the methyl donor

    The overall fold of the catalytic domain of hSET8 is structurally conserved with other SET-domain PKMTs. The SET domain is composed of a single turn 31 0 helix and 12 strands arranged into four antiparallel sheets and a single parallel -sheet. An helix is inserted between the 5- and 6-strands of the SET domain, as is observed in the structures of the histone H3 methyltransferases Neurospora DIM-5 and human SET7/9. This helix forms the inserted SET or iSET region, and variations in the sequence and structure of this motif play a key role in determining the substrate specificity of different PKMTs