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 holo forms, and as a ternary complex with bound products, by X-ray diffraction. The three forms show that the enzyme is a dimer, with each monomer composed of three regions, the nucleotide-binding region, the dimerization region and the catalytic region. The dimerization and catalytic regions have novel folds, whereas the fold of the nucleotide-binding region is a variation on the Rossmann fold. The novel folds impose a novel composition and arrangement of active site residues when compared to all other currently known oxidoreductases. This observation, in conjunction with site-directed mutagenesis of active site residues and steady-state kinetic measurements, suggest that HSD exhibits a new variation on dehydrogenase chemistry.
DeLaBarre
B
B
Antimicrobial Research Centre and Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Thompson
P R
PR
Wright
G D
GD
Berghuis
A M
AM
D001051:Apoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D002412:Cations / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D020035:Holoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006714:Homoserine / Q000378:metabolism; D006715:Homoserine Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006859:Hydrogen / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009243:NAD / Q000031:analogs & derivatives / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D013329:Structure-Activity Relationship
D001051:Apoenzymes; D002412:Cations; D020035:Holoenzymes; D008670:Metals; D009243:NAD; D006714:Homoserine; D006859:Hydrogen; D006715:Homoserine Dehydrogenase