PDBsum entry 1hwx

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Oxidoreductase PDB id
Protein chains
(+ 0 more) 501 a.a. *
GLU ×6
GTP ×6
NAI ×12
Waters ×294
* Residue conservation analysis
Superseded by: 3mw9
PDB id:
Name: Oxidoreductase
Title: Crystal structure of bovine liver glutamate dehydrogenase co with gtp, nadh, and l-glutamic acid
Structure: Glutamate dehydrogenase. Chain: a, b, c, d, e, f. Synonym: gdh. Ec:
Source: Bos taurus. Cattle. Organism_taxid: 9913. Organ: liver. Organelle: mitochondria. Cellular_location: inner mitochondrial matrix
Biol. unit: Hexamer (from PQS)
2.50Å     R-factor:   0.170     R-free:   0.230
Authors: P.E.Peterson,T.J.Smith
Key ref:
P.E.Peterson and T.J.Smith (1999). The structure of bovine glutamate dehydrogenase provides insights into the mechanism of allostery. Structure, 7, 769-782. PubMed id: 10425679 DOI: 10.1016/S0969-2126(99)80101-4
10-Jan-01     Release date:   31-Jan-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P00366  (DHE3_BOVIN) -  Glutamate dehydrogenase 1, mitochondrial
558 a.a.
501 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 17 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Glutamate dehydrogenase (NAD(P)(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-glutamate + H2O + NAD(P)(+) = 2-oxoglutarate + NH3 + NAD(P)H
Bound ligand (Het Group name = GLU)
corresponds exactly
+ H(2)O
Bound ligand (Het Group name = NAI)
matches with 91.00% similarity
= 2-oxoglutarate
+ NH(3)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1016/S0969-2126(99)80101-4 Structure 7:769-782 (1999)
PubMed id: 10425679  
The structure of bovine glutamate dehydrogenase provides insights into the mechanism of allostery.
P.E.Peterson, T.J.Smith.
BACKGROUND: Bovine glutamate dehydrogenase (boGDH) is a homohexameric, mitochondrial enzyme that reversibly catalyzes the oxidative deamination of L-glutamate to 2-oxoglutarate using either NADP(H) or NAD(H) with comparable efficacy. GDH represents a key enzymatic link between catabolic and biosynthetic pathways, and is therefore ubiquitous in both higher and lower organisms. Only mammalian GDH exhibits strong negative cooperativity with respect to the coenzyme, however, and is regulated by a large number of allosteric effectors. RESULTS: The atomic structure of boGDH in complex with NADH, glutamate, and the allosteric inhibitor GTP has been determined to 2.8 A resolution. The major difference between the bacterial and bovine GDH structures is the presence of an additional 'antenna' in boGDH that protrudes from each trimer, twisting counterclockwise along the threefold axis. NADH and glutamate are clearly observed in the active site, but the contacts differ slightly from those observed in Clostridium symbiosum GDH. A second, inhibitory NADH molecule lies buried in the core of the hexamer. Finally, two GTP molecules bind near the hinge region connecting the NAD(+)- and glutamate-binding domains. CONCLUSIONS: We propose that the antenna serves as an intersubunit communication conduit during negative cooperativity and allosteric regulation. GTP and NADH inhibit GDH by keeping the catalytic cleft in a closed conformation. In contrast, ADP probably binds to the back of the NAD(+)-binding domain and activates the enzyme by keeping the catalytic cleft open. Extensive contacts between antennae within the crystal lattice may represent hexamer interactions in solution and, perhaps, with other enzymes within the mitochondrial matrix.
  Selected figure(s)  
Figure 8.
Figure 8. Location of the genetic defects found in human GDH that lead to hyperammonemia and hyperinsulinism. The view and color scheme are the same as inFigure 2. The GTP #1 molecule is represented by a ball-and-stick model; the sidechains of residues observed to mutate in human GDH are shown in stick form. (The figure was created using MolView [31].)
  The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 769-782) copyright 1999.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21428913 P.C.Engel (2011).
Making biochemistry count: life among the amino acid dehydrogenases.
  Biochem Soc Trans, 39, 425-429.  
20697932 J.R.Treberg, M.E.Brosnan, and J.T.Brosnan (2010).
The simultaneous determination of NAD(H) and NADP(H) utilization by glutamate dehydrogenase.
  Mol Cell Biochem, 344, 253-259.  
20665690 S.A.Wacker, M.J.Bradley, J.Marion, and E.Bell (2010).
Ligand-induced changes in the conformational stability and flexibility of glutamate dehydrogenase and their role in catalysis and regulation.
  Protein Sci, 19, 1820-1829.  
19393024 K.Kanavouras, N.Borompokas, H.Latsoudis, A.Stagourakis, I.Zaganas, and A.Plaitakis (2009).
Mutations in human GLUD2 glutamate dehydrogenase affecting basal activity and regulation.
  J Neurochem, 109, 167-173.  
19531491 M.Li, C.J.Smith, M.T.Walker, and T.J.Smith (2009).
Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics.
  J Biol Chem, 284, 22988-23000.
PDB codes: 3etd 3ete 3etg
18442970 C.Frieden (2008).
A lifetime of kinetics.
  J Biol Chem, 283, 19873-19878.  
18467497 J.B.Carrigan, and P.C.Engel (2008).
The structural basis of proteolytic activation of bovine glutamate dehydrogenase.
  Protein Sci, 17, 1346-1353.  
18261912 L.Swint-Kruse, and H.F.Fisher (2008).
Enzymatic reaction sequences as coupled multiple traces on a multidimensional landscape.
  Trends Biochem Sci, 33, 104-112.  
18078298 S.Bigdeli, A.H.Talasaz, P.Ståhl, H.H.Persson, M.Ronaghi, R.W.Davis, and M.Nemat-Gorgani (2008).
Conformational flexibility of a model protein upon immobilization on self-assembled monolayers.
  Biotechnol Bioeng, 100, 19-27.  
18819805 T.J.Smith, and C.A.Stanley (2008).
Untangling the glutamate dehydrogenase allosteric nightmare.
  Trends Biochem Sci, 33, 557-564.  
17531094 A.Del Sol, M.J.Araúzo-Bravo, D.Amoros, and R.Nussinov (2007).
Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages.
  Genome Biol, 8, R92.  
17650509 A.Faye, C.Esnous, N.T.Price, M.A.Onfray, J.Girard, and C.Prip-Buus (2007).
Rat liver carnitine palmitoyltransferase 1 forms an oligomeric complex within the outer mitochondrial membrane.
  J Biol Chem, 282, 26908-26916.  
17253646 K.Kanavouras, V.Mastorodemos, N.Borompokas, C.Spanaki, and A.Plaitakis (2007).
Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase.
  J Neurosci Res, 85, 1101-1109.  
17924438 K.Kanavouras, V.Mastorodemos, N.Borompokas, C.Spanaki, and A.Plaitakis (2007).
Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase.
  J Neurosci Res, 85, 3398-3406.  
17507377 M.M.Choi, E.A.Kim, S.J.Yang, S.Y.Choi, S.W.Cho, and J.W.Huh (2007).
Amino acid changes within antenna helix are responsible for different regulatory preferences of human glutamate dehydrogenase isozymes.
  J Biol Chem, 282, 19510-19517.  
16476731 C.Li, A.Allen, J.Kwagh, N.M.Doliba, W.Qin, H.Najafi, H.W.Collins, F.M.Matschinsky, C.A.Stanley, and T.J.Smith (2006).
Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.
  J Biol Chem, 281, 10214-10221.  
17173671 E.Jaspard (2006).
A computational analysis of the three isoforms of glutamate dehydrogenase reveals structural features of the isoform EC supporting a key role in ammonium assimilation by plants.
  Biol Direct, 1, 38.  
16344948 S.Cotesta, and M.Stahl (2006).
The environment of amide groups in protein-ligand complexes: H-bonds and beyond.
  J Mol Model, 12, 436-444.  
15967348 L.Blasi, L.Longo, P.P.Pompa, L.Manna, G.Ciccarella, G.Vasapollo, R.Cingolani, R.Rinaldi, A.Rizzello, R.Acierno, C.Storelli, and M.Maffia (2005).
Formation and characterization of glutamate dehydrogenase monolayers on silicon supports.
  Biosens Bioelectron, 21, 30-40.  
15578726 V.Mastorodemos, I.Zaganas, C.Spanaki, M.Bessa, and A.Plaitakis (2005).
Molecular basis of human glutamate dehydrogenase regulation under changing energy demands.
  J Neurosci Res, 79, 65-73.  
15653746 W.Zhang, J.S.Olson, and G.N.Phillips (2005).
Biophysical and kinetic characterization of HemAT, an aerotaxis receptor from Bacillus subtilis.
  Biophys J, 88, 2801-2814.  
15514064 E.Sezgin, D.D.Duvernell, L.M.Matzkin, Y.Duan, C.T.Zhu, B.C.Verrelli, and W.F.Eanes (2004).
Single-locus latitudinal clines and their relationship to temperate adaptation in metabolic genes and derived alleles in Drosophila melanogaster.
  Genetics, 168, 923-931.  
14724273 Z.Dubrovay, Z.Gáspári, E.Hunyadi-Gulyás, K.F.Medzihradszky, A.Perczel, and B.G.Vértessy (2004).
Multidimensional NMR identifies the conformational shift essential for catalytic competence in the 60-kDa Drosophila melanogaster dUTPase trimer.
  J Biol Chem, 279, 17945-17950.  
12414808 S.Aghajanian, M.Hovsepyan, K.F.Geoghegan, B.A.Chrunyk, and P.C.Engel (2003).
A thermally sensitive loop in clostridial glutamate dehydrogenase detected by limited proteolysis.
  J Biol Chem, 278, 1067-1074.  
12578821 S.J.Maniscalco, J.F.Tally, S.W.Harris, and H.F.Fisher (2003).
The direct measurement of thermodynamic parameters of reactive transient intermediates of the L-glutamate dehydrogenase reaction.
  J Biol Chem, 278, 16129-16134.  
12193607 H.Y.Yoon, E.H.Cho, H.Y.Kwon, S.Y.Choi, and S.W.Cho (2002).
Importance of glutamate 279 for the coenzyme binding of human glutamate dehydrogenase.
  J Biol Chem, 277, 41448-41454.  
12022886 H.Y.Yoon, E.Y.Lee, and S.W.Cho (2002).
Cassette mutagenesis and photoaffinity labeling of adenine binding domain of ADP regulatory site within human glutamate dehydrogenase.
  Biochemistry, 41, 6817-6823.  
11950837 I.Zaganas, and A.Plaitakis (2002).
Single amino acid substitution (G456A) in the vicinity of the GTP binding domain of human housekeeping glutamate dehydrogenase markedly attenuates GTP inhibition and abolishes the cooperative behavior of the enzyme.
  J Biol Chem, 277, 26422-26428.  
12324473 I.Zaganas, C.Spanaki, M.Karpusas, and A.Plaitakis (2002).
Substitution of Ser for Arg-443 in the regulatory domain of human housekeeping (GLUD1) glutamate dehydrogenase virtually abolishes basal activity and markedly alters the activation of the enzyme by ADP and L-leucine.
  J Biol Chem, 277, 46552-46558.  
12125925 S.Akutsu, and J.Miyazaki (2002).
Biochemical and immunohistochemical studies on tropomyosin and glutamate dehydrogenase in the chicken liver.
  Zoolog Sci, 19, 275-286.  
11754524 A.Kelly, and C.A.Stanley (2001).
Disorders of glutamate metabolism.
  Ment Retard Dev Disabil Res Rev, 7, 287-295.  
11746417 A.Plaitakis, and I.Zaganas (2001).
Regulation of human glutamate dehydrogenases: implications for glutamate, ammonia and energy metabolism in brain.
  J Neurosci Res, 66, 899-908.  
11231268 B.M.Hayden, and P.C.Engel (2001).
Construction, separation and properties of hybrid hexamers of glutamate dehydrogenase in which five of the six subunits are contributed by the catalytically inert D165S.
  Eur J Biochem, 268, 1173-1180.  
  11600502 E.Y.Lee, H.Y.Yoon, J.Y.Ahn, S.Y.Choi, and S.W.Cho (2001).
Identification of the GTP binding site of human glutamate dehydrogenase by cassette mutagenesis and photoaffinity labeling.
  J Biol Chem, 276, 47930-47936.  
11258921 M.Nakasako, T.Fujisawa, S.Adachi, T.Kudo, and S.Higuchi (2001).
Large-scale domain movements and hydration structure changes in the active-site cleft of unligated glutamate dehydrogenase from Thermococcus profundus studied by cryogenic X-ray crystal structure analysis and small-angle X-ray scattering.
  Biochemistry, 40, 3069-3079.
PDB code: 1euz
11518822 P.De Lonlay, C.Benelli, F.Fouque, A.Ganguly, B.Aral, C.Dionisi-Vici, G.Touati, C.Heinrichs, D.Rabier, P.Kamoun, J.J.Robert, C.Stanley, and J.M.Saudubray (2001).
Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients.
  Pediatr Res, 50, 353-357.  
11389722 S.W.Cho, H.Y.Yoon, J.Y.Ahn, E.Y.Lee, and J.Lee (2001).
Cassette mutagenesis of lysine 130 of human glutamate dehydrogenase. An essential residue in catalysis.
  Eur J Biochem, 268, 3205-3213.  
11099181 B.I.Kurganov (2000).
Analysis of negative cooperativity for glutamate dehydrogenase.
  Biophys Chem, 87, 185-199.  
11087937 M.A.Ciardiello, L.Camardella, V.Carratore, and G.di Prisco (2000).
L-Glutamate dehydrogenase from the antarctic fish Chaenocephalus aceratus. Primary structure, function and thermodynamic characterisation: relationship with cold adaptation.
  Biochim Biophys Acta, 1543, 11-23.  
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.