Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 PMID:15485916. Structural domains comprising this superfamily share the structure of domain 1 of the diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphtamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2. PMID:20559380. Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel beta-sheet with three flanking alpha-helices (or two alpha-helices and one 3(10) helix in the case of domain 2). The two beta-sheets in domain 1 and 2 each contain an additional beta-strand that is antiparallel to the rest of the beta-sheet. Domains 2 and 3 have two additional alpha-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded beta-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the center of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s PMID:20559380.