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This pore is rimmed with several structurally conserved carbonyl oxygens as well as the hydroxyl group of the invariant tyrosine from the carboxyl terminus of the SET domain (Determine 1 ). These carbonyl and hydroxyl oxygens have been proposed to facilitate the switch of the methyl group throughout catalysis 16 , 21 , 24 In addition, tyrosine residues in the lysine-binding clefts of SET7/9 (Tyr245 and Tyr305) and DIM-5 (Tyr178) hydrogen-bond to the lysine ε-amino group, aligning it for a methyltransfer with AdoMet (Figure 4b,c ). Mutation of Tyr245 or Tyr305 in SET7/9 (Figure 4b ) alters its specificity from an H3 K4 mono-methylase to a tri- and di-methylase, respectively sixteen , 21 , whereas an Phe281Tyr mutation in the lysine-binding pocket of DIM-5 (Figure 4c ) converts this protein to an H3 K9 mono- or di-methylase 16 These mutations exemplify the F/Y switch (Determine 1 ) that establishes SET-domain product specificities.