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Oxidoreductase PDB id
1qay
Jmol
Contents
Protein chains
384 a.a. *
Ligands
MEV
NAD
Waters ×61
* Residue conservation analysis
PDB id:
1qay
Name: Oxidoreductase
Title: Ternary complex of pseudomonas mevalonii hmg-coa reductase with mevalonate and NAD+
Structure: Protein (3-hydroxy-3-methylglutaryl-coenzyme a reductase). Chain: a, b. Engineered: yes
Source: Pseudomonas mevalonii. Organism_taxid: 32044. Gene: mvaa. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
2.80Å     R-factor:   0.204     R-free:   0.266
Authors: L.Tabernero,D.A.Bochar,V.W.Rodwell,C.V.Stauffacher
Key ref:
L.Tabernero et al. (1999). Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase. Proc Natl Acad Sci U S A, 96, 7167-7171. PubMed id: 10377386 DOI: 10.1073/pnas.96.13.7167
Date:
07-Apr-99     Release date:   18-Jun-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P13702  (MVAA_PSEMV) -  3-hydroxy-3-methylglutaryl-coenzyme A reductase
Seq:
Struc: 		428 a.a.
384 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.88  - Hydroxymethylglutaryl-CoA reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Mevalonate Biosynthesis
      Reaction: (R)-mevalonate + CoA + 2 NAD+ = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH
(R)-mevalonate
Bound ligand (Het Group name = MEV)
corresponds exactly 		+ CoA
 +
2 × NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly 		= 3-hydroxy-3-methylglutaryl-CoA
 + 2 × NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation reduction   2 terms 
  Biochemical function     oxidoreductase activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.96.13.7167 Proc Natl Acad Sci U S A 96:7167-7171 (1999)
PubMed id: 10377386  
 
 
Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase.
L.Tabernero, D.A.Bochar, V.W.Rodwell, C.V.Stauffacher.
 
  ABSTRACT  
 
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme and the first committed step in the biosynthesis of cholesterol in mammals. We have determined the crystal structures of two nonproductive ternary complexes of HMG-CoA reductase, HMG-CoA/NAD+ and mevalonate/NADH, at 2.8 A resolution. In the structure of the Pseudomonas mevalonii apoenzyme, the last 50 residues of the C terminus (the flap domain), including the catalytic residue His381, were not visible. The structures of the ternary complexes reported here reveal a substrate-induced closing of the flap domain that completes the active site and aligns the catalytic histidine proximal to the thioester of HMG-CoA. The structures also present evidence that Lys267 is critically involved in catalysis and provide insights into the catalytic mechanism.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Scheme of the reaction mechanism proposed for P. mevalonii HMG-CoA reductase. The three steps of the reaction from HMG-CoA to mevalonate are shown, and the roles proposed for the key catalytic residues Lys267, Asp283, Glu83, and His381 are indicated. 		Figure 4.
Fig. 4. Ball and stick diagrams of the HMG-CoA (a and b) and mevalonate (c) substrates in the active site of HMG-CoA reductase. The substrates are shown as stick models with C = orange, N = blue, O = red, and S = yellow. (a) Critical contacts with the enzyme (silver bonds) at the site of cleavage of HMG-CoA (green bonds). The thioester oxygen of the substrate points directly at Lys267, making a strong hydrogen bond with this newly identified catalytic residue. The contact between the catalytic His381 and His385, proposed to aid in the protonation of the CoAS^ group, also is shown. (b) The hydrogen bonding network that holds Lys267 in place. Shown are the first shell of hydrogen bond contacts that involve primarily positive and negatively charged residues. (c) Critical contacts of the catalytic residues with the mevalonate substrate. In this ternary complex, the tetrahedral carbon (C-5) points its OH toward one of the Glu83 carboxylic oxygens, suggesting a change in the primary contact of that oxygen after isomerization. This also suggests that Glu83 may be involved in accepting a proton from mevaldyl-CoA, which should have the same tetrahedral configuration for C-5. This figure was prepared with SETOR (20).
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20067617 B.Manavalan, S.K.Murugapiran, G.Lee, and S.Choi (2010).
Molecular modeling of the reductase domain to elucidate the reaction mechanism of reduction of peptidyl thioester into its corresponding alcohol in non-ribosomal peptide synthetases.
  BMC Struct Biol, 10, 1.  
19778626 S.Li, J.A.Friesen, K.C.Holford, and D.W.Borst (2010).
Methyl farnesoate synthesis in the lobster mandibular organ: the roles of HMG-CoA reductase and farnesoic acid O-methyltransferase.
  Comp Biochem Physiol A Mol Integr Physiol, 155, 49-55.  
18076031 R.Dutoit, J.de Ruyck, V.Durisotti, C.Legrain, E.Jacobs, and J.Wouters (2008).
Overexpression, physicochemical characterization, and modeling of a hyperthermophilic pyrococcus furiosus type 2 IPP isomerase.
  Proteins, 71, 1699-1707.  
15613384 J.R.Bradford, and D.R.Westhead (2005).
Improved prediction of protein-protein binding sites using a support vector machines approach.
  Bioinformatics, 21, 1487-1494.  
15802646 S.S.Doun, J.W.Burgner, S.D.Briggs, and V.W.Rodwell (2005).
Enterococcus faecalis phosphomevalonate kinase.
  Protein Sci, 14, 1134-1139.  
15535874 J.A.Friesen, and V.W.Rodwell (2004).
The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases.
  Genome Biol, 5, 248.  
15028676 M.Hedl, L.Tabernero, C.V.Stauffacher, and V.W.Rodwell (2004).
Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases.
  J Bacteriol, 186, 1927-1932.  
12527789 C.Blouin, Y.Boucher, and A.J.Roger (2003).
Inferring functional constraints and divergence in protein families using 3D mapping of phylogenetic information.
  Nucleic Acids Res, 31, 790-797.  
12460936 S.J.Seybold, and C.Tittiger (2003).
Biochemistry and molecular biology of de novo isoprenoid pheromone production in the Scolytidae.
  Annu Rev Entomol, 48, 425-453.  
  10892815 D.Y.Kim, C.V.Stauffacher, and V.W.Rodwell (2000).
Dual coenzyme specificity of Archaeoglobus fulgidus HMG-CoA reductase.
  Protein Sci, 9, 1226-1234.  
10960099 E.I.Wilding, D.Y.Kim, A.P.Bryant, M.N.Gwynn, R.D.Lunsford, D.McDevitt, J.E.Myers, M.Rosenberg, D.Sylvester, C.V.Stauffacher, and V.W.Rodwell (2000).
Essentiality, expression, and characterization of the class II 3-hydroxy-3-methylglutaryl coenzyme A reductase of Staphylococcus aureus.
  J Bacteriol, 182, 5147-5152.  
10894743 E.I.Wilding, J.R.Brown, A.P.Bryant, A.F.Chalker, D.J.Holmes, K.A.Ingraham, S.Iordanescu, C.Y.So, M.Rosenberg, and M.N.Gwynn (2000).
Identification, evolution, and essentiality of the mevalonate pathway for isopentenyl diphosphate biosynthesis in gram-positive cocci.
  J Bacteriol, 182, 4319-4327.  
11111074 E.S.Istvan, and J.Deisenhofer (2000).
The structure of the catalytic portion of human HMG-CoA reductase.
  Biochim Biophys Acta, 1529, 9.  
10698924 E.S.Istvan, M.Palnitkar, S.K.Buchanan, and J.Deisenhofer (2000).
Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
  EMBO J, 19, 819-830.
PDB codes: 1dq8 1dq9 1dqa
10841783 R.E.Campbell, S.C.Mosimann, I.van De Rijn, M.E.Tanner, and N.C.Strynadka (2000).
The first structure of UDP-glucose dehydrogenase reveals the catalytic residues necessary for the two-fold oxidation.
  Biochemistry, 39, 7012-7023.
PDB codes: 1dli 1dlj
  10512876 D.A.Profant, C.J.Roberts, A.J.Koning, and R.L.Wright (1999).
The role of the 3-hydroxy 3-methylglutaryl coenzyme A reductase cytosolic domain in karmellae biogenesis.
  Mol Biol Cell, 10, 3409-3423.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.