PDBsum entry 1ebf

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Oxidoreductase PDB id
Protein chains
358 a.a. *
_NA ×2
Waters ×253
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Homoserine dehydrogenase from s. Cerevisiae complex with NAD+
Structure: Homoserine dehydrogenase. Chain: a, b. Engineered: yes
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Gene: hom6p. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
2.30Å     R-factor:   0.218     R-free:   0.269
Authors: B.Delabarre,P.R.Thompson,G.D.Wright,A.M.Berghuis
Key ref:
B.DeLaBarre et al. (2000). Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases. Nat Struct Biol, 7, 238-244. PubMed id: 10700284 DOI: 10.1038/73359
24-Jan-00     Release date:   08-Mar-00    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P31116  (DHOM_YEAST) -  Homoserine dehydrogenase
359 a.a.
358 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Homoserine dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Threonine Biosynthesis
      Reaction: L-homoserine + NAD(P)(+) = L-aspartate 4-semialdehyde + NAD(P)H
Bound ligand (Het Group name = NAD)
matches with 91.00% similarity
= L-aspartate 4-semialdehyde
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   8 terms 
  Biochemical function     oxidoreductase activity     3 terms  


DOI no: 10.1038/73359 Nat Struct Biol 7:238-244 (2000)
PubMed id: 10700284  
Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases.
B.DeLaBarre, P.R.Thompson, G.D.Wright, A.M.Berghuis.
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.
  Selected figure(s)  
Figure 1.
Figure 1. Electron density maps for the two crystal forms of HSD. a, Stereo view of a 2F[o]- F[c] electron density map calculated with coefficients from the final tetragonal crystal form model and contoured at 1 . The portion of the molecule shown here is the dimer interfacial region of the extended -sheet and is composed of residues 320 -335 from monomer A, and residues 332 -335 and 319 -325 from monomer B. b, Stereo view of the F[o]- F[c] simulated annealing omit map for the NAD^+ molecule in the tetragonal crystal form, contoured at 2 . c, Stereo view of the F[o]- F[c] simulated annealing omit map for the NADA and l-Hse molecules in the monoclinic crystal form, contoured at 2 .
Figure 5.
Figure 5. Proposed reaction mechanisms of hydride transfer for HSD. a, Probable reaction mechanism for the forward direction with the substrate in the aldehyde form. Asp 214, Glu 208 and Wat460 serve to bind the substrate, whereas Lys 223, oriented by Asp 219, donates a proton to the C4 oxygen of l-ASA. The cofactor NADH delivers its pro-S hydride to the C4 carbon of l-ASA. Arrows indicate electron flow. b, Alternative reaction mechanism for the forward direction with the substrate in the gem-diol form. The main difference from the reaction proposed for the aldehyde form is that Lys 223 donates a proton to the hydroxyl group, which departs as a water molecule, and Asp 219 hydrogen bonds to the hydroxyl group, which remains in the product alcohol.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 238-244) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20660776 F.J.Sangari, J.Pérez-Gil, L.Carretero-Paulet, J.M.García-Lobo, and M.Rodríguez-Concepción (2010).
A new family of enzymes catalyzing the first committed step of the methylerythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis in bacteria.
  Proc Natl Acad Sci U S A, 107, 14081-14086.  
19946135 C.C.Lo, C.A.Bonner, G.Xie, M.D'Souza, and R.A.Jensen (2009).
Cohesion group approach for evolutionary analysis of aspartokinase, an enzyme that feeds a branched network of many biochemical pathways.
  Microbiol Mol Biol Rev, 73, 594-651.  
16267046 E.Di Cera (2006).
A structural perspective on enzymes activated by monovalent cations.
  J Biol Chem, 281, 1305-1308.  
14579323 L.N.Kinch, Y.Qi, T.J.Hubbard, and N.V.Grishin (2003).
CASP5 target classification.
  Proteins, 53, 340-351.  
14583265 S.L.Jacques, I.A.Mirza, L.Ejim, K.Koteva, D.W.Hughes, K.Green, R.Kinach, J.F.Honek, H.K.Lai, A.M.Berghuis, and G.D.Wright (2003).
Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase.
  Chem Biol, 10, 989-995.
PDB code: 1q7g
12461183 H.Ogawa, and C.Toyoshima (2002).
Homology modeling of the cation binding sites of Na+K+-ATPase.
  Proc Natl Acad Sci U S A, 99, 15977-15982.  
11341915 S.L.Jacques, L.J.Ejim, and G.D.Wright (2001).
Homoserine dehydrogenase from Saccharomyces cerevisiae: kinetic mechanism and stereochemistry of hydride transfer.
  Biochim Biophys Acta, 1544, 42-54.  
11080625 E.Johansson, J.J.Steffens, Y.Lindqvist, and G.Schneider (2000).
Crystal structure of saccharopine reductase from Magnaporthe grisea, an enzyme of the alpha-aminoadipate pathway of lysine biosynthesis.
  Structure, 8, 1037-1047.
PDB codes: 1e5l 1e5q 1ff9
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