A recent publication from the David, Siegel and Lim (Academia Sinica, Taiwan) labs (Nuñez et al., JACS, 2018) provides insight into the coordination sphere and critical role of a Zn²⁺ metal binding site in the DNA repair glycosylase MUTYH. Genome database mining and sequence alignment of MUTYH orthologs, along with computational modeling, identified and supported Zn²⁺ ligation by four Cys residues. Three of the Cys residues lie in an interdomain connector region unique to mammalian MutY enzymes, while the 4th Cys is located in close proximity to the Fe-S cluster DNA binding domain.