Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases

The structure of the antifungal drug target homoserine dehydrogenase (HSD) was determined from Saccharomyces cerevisiae in apo and hole forms, and as a ternary complex with bound products, by X-ray diffraction. The three form s show that the enzyme is a dimer, with each monomer composed of three regi ons, the nucleotide-binding region, the dimerization region and the catalyt ic region. The dimerization and catalytic regions have novel folds, whereas the fold of the nucleotide-binding region is a variation on the Rossmann f old. The novel folds impose a novel composition and arrangement of active s ite residues when compared to all other currently known oxidoreductases. Th is observation, in conjunction with site-directed mutagenesis of active sit e residues and steady-state kinetic measurements, suggest that HSD exhibits a new variation on dehydrogenase chemistry.