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Mutation of Tyr245 or Tyr305 in SET7/9 (Determine 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 (Determine 4c ) converts this protein to an H3 K9 mono- or di-methylase 16 These mutations exemplify the F/Y change (Determine 1 ) that establishes SET-domain product specificities. These carbonyl and hydroxyl oxygens have been proposed to facilitate the switch of the methyl group throughout catalysis sixteen , 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 (Determine 4b,c ). 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 ).
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