Although in all three studies, electron density maps revealed the location of the AdoMet or AdoHcy cofactor, the SET domain bears no similarity at all to the canonical/AdoMet-dependent methyltransferase fold.

In contrast to the AdoMet-dependent protein methyltranferases of the classical type, which tend to bind their polypeptide substrates on top of the cofactor, it is noted from the Rubisco LSMT structure that the AdoMet seems to bind in a separate cleft, suggesting how a polypeptide substrate could be subjected to multiple rounds of methylation without having to be released from the enzyme.

[2] The SET domain-containing Drosophila melanogaster (Fruit fly) protein, enhancer of zeste, has a function in segment determination and the mammalian homologue may be involved in the regulation of gene transcription and chromatin structure.

[6] The N-terminal pre-SET domain (InterPro: IPR007728), as found in the SUV39 SET family, contains nine invariant cysteine residues that are grouped into two segments separated by a region of variable length.

The C-terminal region including the post-SET domain (InterPro: IPR003616) is disordered when not interacting with a histone tail and in the absence of zinc.