vSET (a viral SET domain protein) is an attractive polycomb repressive complex 2 
(PRC2) surrogate to study the effect of histone H3 lysine 27 (H3K27) methylation 
on gene transcription, as both catalyze histone H3K27 trimethylation. To control 
the enzymatic activity of vSET in vivo with an engineered 
S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried 
out structure-guided design, synthesis, and characterization of orthogonal vSET 
methyltransferase mutant/SAM analogue pairs using a "bump-and-hole" strategy.