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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Apoenzymes; Binding Sites; Catalysis; Catalytic Domain; Cations; Crystallography, X-Ray; Dimerization; Holoenzymes; Homoserine; Homoserine Dehydrogenase; Hydrogen; Metals; *Models, Chemical; Models, Molecular; Molecular Sequence Data; Mutation; NAD; Protein Conformation; Protein Folding; Saccharomyces cerevisiae; Structure-Activity Relationship


Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics


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.

DOI of Published Version



Nat Struct Biol. 2000 Mar;7(3):238-44. Link to article on publisher's site

Journal/Book/Conference Title

Nature structural biology


At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed