Cysteine dioxygenase (CDO) is a mammalian enzyme critical for maintaining sufficiently low levels of the amino acid cysteine, which is toxic in abundance. Human CDO in its mature form contains a cross-link between an active site cysteine and tyrosine residue which significantly increases catalytic efficiency. This week's seminar will showcase differences between the heretofore unsolved structures of human CDO after formation of the cross-link cofactor and/or ligand binding. Genetic incorporation of unnatural amino acids was used to probe cofactor formation without disturbing the enzyme active site. These results suggest a way that the post-translationally generated human CDO cofactor improves enzyme efficiency and, interestingly, could aid in the development of designer carbon-halogen biochemistry.