In eukaryotes, DNA methylation is an important epigenetic modification that is 
generally involved in gene regulation. Methyltransferases (MTases) of the DNMT2 
family have been shown to have a dual substrate specificity acting on DNA as 
well as on three specific tRNAs (tRNA(Asp), tRNA(Val), tRNA(Gly)). Entamoeba 
histolytica is a major human pathogen, and expresses a single DNA MTase (EhMeth) 
that belongs to the DNMT2 family and shows high homology to the human enzyme as 
well as to the bacterial DNA MTase M.HhaI. The molecular basis for the 
recognition of the substrate tRNAs and discrimination of non-cognate tRNAs is 
unknown. Here we present the crystal structure of the 
cytosine-5-methyltransferase EhMeth at a resolution of 2.15 Å, in complex with 
its reaction product S-adenosyl-L-homocysteine, revealing all parts of a DNMT2 
MTase, including the active site loop. Mobility shift assays show that in vitro 
the full length tRNA is required for stable complex formation with EhMeth.