Title

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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2000-03-01

Document Type

Article

Subjects

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

Disciplines

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

Abstract

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

10.1038/73359

Source

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

Journal/Book/Conference Title

Nature structural biology

Comments

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

Related Resources

Link to Article in PubMed

Link to Full Text

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