PDBsum entry 1ikb

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Oxidoreductase(NAD(a)-choh(d)) PDB id
Jmol PyMol
Protein chain
414 a.a.
Waters ×2
Superseded by: 1ai2 1ai2
PDB id:
Name: Oxidoreductase(NAD(a)-choh(d))
Structure: Isocitrate dehydrogenase complexed with isocitrate, NADP, and calcium
Source: (Escherichia coli)
Biol. unit: Dimer (from PQS)
Authors: B.L.Stoddard,D.E.Koshland Junior
Key ref:
B.L.Stoddard et al. (1993). Structure of isocitrate dehydrogenase with isocitrate, nicotinamide adenine dinucleotide phosphate, and calcium at 2.5-A resolution: a pseudo-Michaelis ternary complex. Biochemistry, 32, 9310-9316. PubMed id: 8369300 DOI: 10.1021/bi00087a008
15-Jun-93     Release date:   31-Jul-94    
Go to PROCHECK summary

Protein chain
No UniProt id for this chain
Struc: 414 a.a.
Key:    Secondary structure  CATH domain


DOI no: 10.1021/bi00087a008 Biochemistry 32:9310-9316 (1993)
PubMed id: 8369300  
Structure of isocitrate dehydrogenase with isocitrate, nicotinamide adenine dinucleotide phosphate, and calcium at 2.5-A resolution: a pseudo-Michaelis ternary complex.
B.L.Stoddard, A.Dean, D.E.Koshland.
The structure of isocitrate dehydrogenase (IDH) with a bound complex of isocitrate, NADP+, and Ca2+ was solved at 2.5-A resolution and compared by difference mapping against previously determined enzymatic complexes. Calcium replaces magnesium in the binding of metal-substrate chelate complex, resulting in a substantially reduced turnover rate. The structure shows the following: (i) A complete, structurally ordered ternary complex (enzyme, isocitrate, NADP+, and Ca2+) is observed in the active site, with the nicotinamide ring of NADP+ exhibiting a specific salt bridge with isocitrate. The binding of the cofactor nicotinamide ring is dependent on this interaction. (ii) Isocitrate is bound by the enzyme with the same interactions as those found for the magnesium/substrate binary complex, but the entire molecule is shifted in the active site by approximately 1 A in order to accommodate the larger metal species and to interact with the nicotinamide ring. The distances from isocitrate to the bound calcium are substantially longer than those previously found with magnesium. (iii) NADP in the Escherichia coli IDH has a novel binding site and conformation as compared to previously solved dehydrogenases. (iv) The orientation and interactions of the nicotinamide ring with the substrate are consistent with the stereospecificity of the enzyme-catalyzed reaction.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20516620 R.Malik, and R.E.Viola (2010).
Structural characterization of tartrate dehydrogenase: a versatile enzyme catalyzing multiple reactions.
  Acta Crystallogr D Biol Crystallogr, 66, 673-684.
PDB codes: 3flk 3fmx
17634983 K.Imada, T.Tamura, R.Takenaka, I.Kobayashi, K.Namba, and K.Inagaki (2008).
Structure and quantum chemical analysis of NAD+-dependent isocitrate dehydrogenase: hydride transfer and co-factor specificity.
  Proteins, 70, 63-71.
PDB code: 2d4v
18552125 Y.Peng, C.Zhong, W.Huang, and J.Ding (2008).
Structural studies of Saccharomyces cerevesiae mitochondrial NADP-dependent isocitrate dehydrogenase in different enzymatic states reveal substantial conformational changes during the catalytic reaction.
  Protein Sci, 17, 1542-1554.
PDB codes: 2qfv 2qfw 2qfx 2qfy
17401542 R.Stokke, M.Karlström, N.Yang, I.Leiros, R.Ladenstein, N.K.Birkeland, and I.H.Steen (2007).
Thermal stability of isocitrate dehydrogenase from Archaeoglobus fulgidus studied by crystal structure analysis and engineering of chimers.
  Extremophiles, 11, 481-493.
PDB code: 2iv0
16416443 F.Imabayashi, S.Aich, L.Prasad, and L.T.Delbaere (2006).
Substrate-free structure of a monomeric NADP isocitrate dehydrogenase: an open conformation phylogenetic relationship of isocitrate dehydrogenase.
  Proteins, 63, 100-112.
PDB code: 2b0t
16737955 S.Soundar, M.O'hagan, K.S.Fomulu, and R.F.Colman (2006).
Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase.
  J Biol Chem, 281, 21073-21081.  
16342968 S.L.Anderson, A.P.Lin, and L.McAlister-Henn (2005).
Analysis of interactions with mitochondrial mRNA using mutant forms of yeast NAD(+)-specific isocitrate dehydrogenase.
  Biochemistry, 44, 16776-16784.  
15975917 Y.C.Huang, and R.F.Colman (2005).
Location of the coenzyme binding site in the porcine mitochondrial NADP-dependent isocitrate dehydrogenase.
  J Biol Chem, 280, 30349-30353.  
15173171 X.Xu, J.Zhao, Z.Xu, B.Peng, Q.Huang, E.Arnold, and J.Ding (2004).
Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity.
  J Biol Chem, 279, 33946-33957.
PDB codes: 1t09 1t0l
12562755 A.P.Lin, and L.McAlister-Henn (2003).
Homologous binding sites in yeast isocitrate dehydrogenase for cofactor (NAD+) and allosteric activator (AMP).
  J Biol Chem, 278, 12864-12872.  
14555658 S.Soundar, J.H.Park, T.L.Huh, and R.F.Colman (2003).
Evaluation by mutagenesis of the importance of 3 arginines in alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase.
  J Biol Chem, 278, 52146-52153.  
12855708 Y.Yasutake, S.Watanabe, M.Yao, Y.Takada, N.Fukunaga, and I.Tanaka (2003).
Crystal structure of the monomeric isocitrate dehydrogenase in the presence of NADP+: insight into the cofactor recognition, catalysis, and evolution.
  J Biol Chem, 278, 36897-36904.
PDB code: 1j1w
12207025 C.Ceccarelli, N.B.Grodsky, N.Ariyaratne, R.F.Colman, and B.J.Bahnson (2002).
Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism.
  J Biol Chem, 277, 43454-43462.
PDB code: 1lwd
12454487 M.Karlström, I.H.Steen, G.Tibbelin, T.Lien, N.K.Birkeland, and R.Ladenstein (2002).
Crystallization and preliminary X-ray structure analysis of isocitrate dehydrogenase from two hyperthermophiles, Aeropyrum pernix and Thermotoga maritima.
  Acta Crystallogr D Biol Crystallogr, 58, 2162-2164.  
11751849 S.K.Singh, S.P.Miller, A.Dean, L.J.Banaszak, and D.C.LaPorte (2002).
Bacillus subtilis isocitrate dehydrogenase. A substrate analogue for Escherichia coli isocitrate dehydrogenase kinase/phosphatase.
  J Biol Chem, 277, 7567-7573.  
12005040 T.Sahara, Y.Takada, Y.Takeuchi, N.Yamaoka, and N.Fukunaga (2002).
Cloning, sequencing, and expression of a gene encoding the monomeric isocitrate dehydrogenase of the nitrogen-fixing bacterium, Azotobacter vinelandii.
  Biosci Biotechnol Biochem, 66, 489-500.  
11533060 I.H.Steen, D.Madern, M.Karlström, T.Lien, R.Ladenstein, and N.K.Birkeland (2001).
Comparison of isocitrate dehydrogenase from three hyperthermophiles reveals differences in thermostability, cofactor specificity, oligomeric state, and phylogenetic affiliation.
  J Biol Chem, 276, 43924-43931.  
11455601 K.A.Denessiouk, V.V.Rantanen, and M.S.Johnson (2001).
Adenine recognition: a motif present in ATP-, CoA-, NAD-, NADP-, and FAD-dependent proteins.
  Proteins, 44, 282-291.  
11284679 S.A.Doyle, P.T.Beernink, and D.E.Koshland (2001).
Structural basis for a change in substrate specificity: crystal structure of S113E isocitrate dehydrogenase in a complex with isopropylmalate, Mg2+, and NADP.
  Biochemistry, 40, 4234-4241.
PDB code: 1hj6
10677231 C.Weiss, Y.Zeng, J.Huang, M.B.Sobocka, and J.I.Rushbrook (2000).
Bovine NAD+-dependent isocitrate dehydrogenase: alternative splicing and tissue-dependent expression of subunit 1.
  Biochemistry, 39, 1807-1816.  
10694384 N.B.Grodsky, S.Soundar, and R.F.Colman (2000).
Evaluation by site-directed mutagenesis of aspartic acid residues in the metal site of pig heart NADP-dependent isocitrate dehydrogenase.
  Biochemistry, 39, 2193-2200.  
  11206056 R.Chen, and S.S.Jeong (2000).
Functional prediction: identification of protein orthologs and paralogs.
  Protein Sci, 9, 2344-2353.  
10681542 S.Soundar, B.L.Danek, and R.F.Colman (2000).
Identification by mutagenesis of arginines in the substrate binding site of the porcine NADP-dependent isocitrate dehydrogenase.
  J Biol Chem, 275, 5606-5612.  
10215879 J.Olano, J.Soler, F.Busto, and D.De Arriaga (1999).
Chemical modification of NADP-isocitrate dehydrogenase from Cephalosporium acremonium evidence of essential histidine and lysine groups at the active site.
  Eur J Biochem, 261, 640-649.  
9891796 A.J.Cozzone (1998).
Regulation of acetate metabolism by protein phosphorylation in enteric bacteria.
  Annu Rev Microbiol, 52, 127-164.  
9739088 K.Imada, K.Inagaki, H.Matsunami, H.Kawaguchi, H.Tanaka, N.Tanaka, and K.Namba (1998).
Structure of 3-isopropylmalate dehydrogenase in complex with 3-isopropylmalate at 2.0 A resolution: the role of Glu88 in the unique substrate-recognition mechanism.
  Structure, 6, 971-982.
PDB code: 1a05
9694855 M.H.Eppink, H.A.Schreuder, and W.J.van Berkel (1998).
Interdomain binding of NADPH in p-hydroxybenzoate hydroxylase as suggested by kinetic, crystallographic and modeling studies of histidine 162 and arginine 269 variants.
  J Biol Chem, 273, 21031-21039.
PDB codes: 1bgj 1bgn
9220992 B.E.Cohen, B.L.Stoddard, and D.E.Koshland (1997).
Caged NADP and NAD. Synthesis and characterization of functionally distinct caged compounds.
  Biochemistry, 36, 9035-9044.  
  9336832 C.E.Bell, T.O.Yeates, and D.Eisenberg (1997).
Unusual conformation of nicotinamide adenine dinucleotide (NAD) bound to diphtheria toxin: a comparison with NAD bound to the oxidoreductase enzymes.
  Protein Sci, 6, 2084-2096.  
9428712 R.Chen, A.F.Greer, and A.M.Dean (1997).
Structural constraints in protein engineering--the coenzyme specificity of Escherichia coli isocitrate dehydrogenase.
  Eur J Biochem, 250, 578-582.  
  8745412 A.M.Dean, A.K.Shiau, and D.E.Koshland (1996).
Determinants of performance in the isocitrate dehydrogenase of Escherichia coli.
  Protein Sci, 5, 341-347.  
8673602 B.L.Stoddard, A.Dean, and P.A.Bash (1996).
Combining Laue diffraction and molecular dynamics to study enzyme intermediates.
  Nat Struct Biol, 3, 590-595.  
8885829 B.Sankaran, A.J.Chavan, and B.E.Haley (1996).
Identification of adenine binding domain peptides of the NADP+ active site within porcine heart NADP(+)-dependent isocitrate dehydrogenase.
  Biochemistry, 35, 13501-13510.  
8639526 J.H.Hurley, R.Chen, and A.M.Dean (1996).
Determinants of cofactor specificity in isocitrate dehydrogenase: structure of an engineered NADP+ --> NAD+ specificity-reversal mutant.
  Biochemistry, 35, 5670-5678.
PDB code: 1iso
8608121 M.J.Brubaker, D.H.Dyer, B.Stoddard, and D.E.Koshland (1996).
Synthesis, kinetics, and structural studies of a photolabile caged isocitrate: a catalytic trigger for isocitrate dehydrogenase.
  Biochemistry, 35, 2854-2864.  
  8844853 P.A.Tipton, T.P.Quinn, J.Peisach, and P.F.Cook (1996).
Role of the divalent metal ion in the NAD:malic enzyme reaction: an ESEEM determination of the ground state conformation of malate in the E:Mn:malate complex.
  Protein Sci, 5, 1648-1654.  
  8745413 T.Zhang, and D.E.Koshland (1996).
Computational method for relative binding energies of enzyme-substrate complexes.
  Protein Sci, 5, 348-356.  
8524825 R.Chen, A.Greer, and A.M.Dean (1995).
A highly active decarboxylating dehydrogenase with rationally inverted coenzyme specificity.
  Proc Natl Acad Sci U S A, 92, 11666-11670.  
7819280 R.S.Ehrlich, and R.F.Colman (1995).
Cadmium-113 and magnesium-25 NMR study of the divalent metal binding sites of isocitrate dehydrogenases from pig heart.
  Biochim Biophys Acta, 1246, 135-141.  
  7773180 T.Zhang, and D.E.Koshland (1995).
Modeling substrate binding in Thermus thermophilus isopropylmalate dehydrogenase.
  Protein Sci, 4, 84-92.  
7881901 J.H.Hurley, and A.M.Dean (1994).
Structure of 3-isopropylmalate dehydrogenase in complex with NAD+: ligand-induced loop closing and mechanism for cofactor specificity.
  Structure, 2, 1007-1016.
PDB code: 1hex
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.