PRMTs (A), small-molecule methyltransferases (B), DOT1L (C), and DNMTs (D) share a common SAM binding fold (dashed-line square). A structural element variable in length and geometry (orange), immediately upstream of this conserved fold, covers the bound cofactor (cyan), contributes to formation of the site of methyl transfer (solid-line square), and to the recruitment of the methyl-accepting substrate (indicated in green by the co-crystallized substrate in B). In the absence of cofactor (A) or in the absence of the cofactor’s homocysteine end (C), this element can adopt different conformations (blue) that alter the binding pocket of SAM. The specificity of substrate recruitment and accuracy of substrate presentation relies on the nature of this critical and diverse structural element. PDB codes: CARM1: 3b3f (orange), 3b3j (blue), COMT: 1vid, DOT1L; 1nw3 (orange), 3uwp (blue); DNMT: 3pta. (structurally diverse domains not participating in cofactor binding were removed, and DNA substrate is not shown in D, for clarity).