B. Delabarre et al., Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases, NAT ST BIOL, 7(3), 2000, pp. 238-244
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.