Crystal structure of shikimate 5-dehydrogenase (SDH) bound to NADP: insights into function and evolution.
The crystal structure of Methanococcus jannaschii shikimate 5-dehydrogenase (MjSDH) bound to the cofactor nicotinamide adenine dinucleotide phosphate (NADP) has been determined at 2.35 A resolution. Shikimate 5-dehydrogenase (SDH) is responsible for NADP-dependent catalysis of the fourth step in shikimate biosynthesis, which is essential for aromatic amino acid metabolism in bacteria, microbial eukaryotes, and plants. The structure of MjSDH is a compact alpha/beta sandwich with two distinct domains, responsible for binding substrate and the NADP cofactor, respectively. A phylogenetically conserved deep cleft on the protein surface corresponds to the enzyme active site. The structure reveals a topologically new domain fold within the N-terminal segment of the polypeptide chain, which binds substrate and supports dimerization. Insights gained from homology modeling and sequence/structure comparisons suggest that the SDHs represent a unique class of dehydrogenases. The structure provides a framework for further investigation to discover and develop novel inhibitors targeting this essential enzyme.
Padyana
Anil K
AK
Laboratories of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Burley
Stephen K
SK
D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D019143:Evolution, Molecular; D006860:Hydrogen Bonding; D017017:Methanococcus / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism*; D010802:Phylogeny; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012765:Shikimic Acid / Q000378:metabolism; D013059:Spectrum Analysis, Raman; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
D014867:Water; D012765:Shikimic Acid; D009249:NADP; D000429:Alcohol Oxidoreductases; C022641:Shikimate dehydrogenase