PDBsum entry 1t09

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Oxidoreductase PDB id
Protein chain
414 a.a. *
NAP ×2
Waters ×155
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of human cytosolic NADP(+)-dependent isocitrate dehydrogenase in complex NADP
Structure: Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: a, b. Synonym: cytosolic NADP(+)-dependent isocitrate dehydrogenase, oxalosuccinate decarboxylase, idh, NADP+- specific icdh, idp. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: idh. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
2.70Å     R-factor:   0.210     R-free:   0.270
Authors: X.Xu,J.Zhao,B.Peng,Q.Huang,E.Arnold,J.Ding
Key ref:
X.Xu et al. (2004). Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem, 279, 33946-33957. PubMed id: 15173171 DOI: 10.1074/jbc.M404298200
08-Apr-04     Release date:   15-Jun-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O75874  (IDHC_HUMAN) -  Isocitrate dehydrogenase [NADP] cytoplasmic
414 a.a.
414 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Isocitrate dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
Bound ligand (Het Group name = NAP)
corresponds exactly
= 2-oxoglutarate
+ CO(2)
      Cofactor: Mn(2+) or Mg(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   6 terms 
  Biological process     small molecule metabolic process   13 terms 
  Biochemical function     oxidoreductase activity     9 terms  


DOI no: 10.1074/jbc.M404298200 J Biol Chem 279:33946-33957 (2004)
PubMed id: 15173171  
Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity.
X.Xu, J.Zhao, Z.Xu, B.Peng, Q.Huang, E.Arnold, J.Ding.
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their regulatory mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved alpha-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH; a partially unraveled alpha-helix in the semi-open, intermediate form; and an alpha-helix in the closed, active form. The side chain of Asp279 of this segment occupies the isocitrate-binding site and forms hydrogen bonds with Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-regulatory mechanism for HcIDH that mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.
  Selected figure(s)  
Figure 5.
FIG. 5. Conformational differences at the active site. A, subunit A of the HcIDH binary complex. B, subunit B of the HcIDH binary complex. C, subunit A of the HcIDH quaternary complex. D, structure of the PmIDH-isocitrate-Mn2+ complex (Protein Data Bank code 1LWD [PDB] ). E, structure of the EcIDH-NADP-isocitrate-Ca^2+ complex (Protein Data Bank code 1AI2 [PDB] ). F, structure of the BsIDH-citrate complex (Protein Data Bank code 1HQS [PDB] ). Isocitrate (ICT, in gold), NADP (in magenta), and the side chains of several important residues (in green) are shown with ball-and-stick models, and metal ions appear as spheres (in cyan).
Figure 6.
FIG. 6. Schematic diagram of the conformational changes during the regulation of HcIDH activity. The competitive binding of isocitrate (and metal ion) induces the conformational changes.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 33946-33957) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20171178 A.K.Murugan, E.Bojdani, and M.Xing (2010).
Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer.
  Biochem Biophys Res Commun, 393, 555-559.  
20410924 A.Pardanani, T.L.Lasho, C.M.Finke, M.Mai, R.F.McClure, and A.Tefferi (2010).
IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms.
  Leukemia, 24, 1146-1151.  
20975740 B.Yang, C.Zhong, Y.Peng, Z.Lai, and J.Ding (2010).
Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.
  Cell Res, 20, 1188-1200.
PDB codes: 3map 3mar 3mas
20127344 F.E.Bleeker, N.A.Atai, S.Lamba, A.Jonker, D.Rijkeboer, K.S.Bosch, W.Tigchelaar, D.Troost, W.P.Vandertop, A.Bardelli, and C.J.Van Noorden (2010).
The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma.
  Acta Neuropathol, 119, 487-494.  
20972461 K.E.Yen, M.A.Bittinger, S.M.Su, and V.R.Fantin (2010).
Cancer-associated IDH mutations: biomarker and therapeutic opportunities.
  Oncogene, 29, 6409-6417.  
20692206 L.Dang, S.Jin, and S.M.Su (2010).
IDH mutations in glioma and acute myeloid leukemia.
  Trends Mol Med, 16, 387-397.  
20376084 O.Kosmider, V.Gelsi-Boyer, L.Slama, F.Dreyfus, O.Beyne-Rauzy, B.Quesnel, M.Hunault-Berger, B.Slama, N.Vey, C.Lacombe, E.Solary, D.Birnbaum, O.A.Bernard, and M.Fontenay (2010).
Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms.
  Leukemia, 24, 1094-1096.  
  20847279 P.Setty, J.Hammes, T.Rothämel, V.Vladimirova, C.M.Kramm, T.Pietsch, and A.Waha (2010).
A pyrosequencing-based assay for the rapid detection of IDH1 mutations in clinical samples.
  J Mol Diagn, 12, 750-756.  
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
20142433 S.Gross, R.A.Cairns, M.D.Minden, E.M.Driggers, M.A.Bittinger, H.G.Jang, M.Sasaki, S.Jin, D.P.Schenkein, S.M.Su, L.Dang, V.R.Fantin, and T.W.Mak (2010).
Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.
  J Exp Med, 207, 339-344.  
21045797 T.D.Bourne, and D.Schiff (2010).
Update on molecular findings, management and outcome in low-grade gliomas.
  Nat Rev Neurol, 6, 695-701.  
20367200 Y.Sonoda, and T.Tominaga (2010).
2-hydroxyglutarate accumulation caused by IDH mutation is involved in the formation of malignant gliomas.
  Expert Rev Neurother, 10, 487-489.  
20513808 Z.J.Reitman, and H.Yan (2010).
Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.
  J Natl Cancer Inst, 102, 932-941.  
19228626 C.B.Thompson (2009).
Metabolic enzymes as oncogenes or tumor suppressors.
  N Engl J Med, 360, 813-815.  
19117336 F.E.Bleeker, S.Lamba, S.Leenstra, D.Troost, T.Hulsebos, W.P.Vandertop, M.Frattini, F.Molinari, M.Knowles, A.Cerrato, M.Rodolfo, A.Scarpa, L.Felicioni, F.Buttitta, S.Malatesta, A.Marchetti, and A.Bardelli (2009).
IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.
  Hum Mutat, 30, 7.  
19996293 H.Yan, D.D.Bigner, V.Velculescu, and D.W.Parsons (2009).
Mutant metabolic enzymes are at the origin of gliomas.
  Cancer Res, 69, 9157-9159.  
19228619 H.Yan, D.W.Parsons, G.Jin, R.McLendon, B.A.Rasheed, W.Yuan, I.Kos, I.Batinic-Haberle, S.Jones, G.J.Riggins, H.Friedman, A.Friedman, D.Reardon, J.Herndon, K.W.Kinzler, V.E.Velculescu, B.Vogelstein, and D.D.Bigner (2009).
IDH1 and IDH2 mutations in gliomas.
  N Engl J Med, 360, 765-773.  
19435942 K.Ichimura, D.M.Pearson, S.Kocialkowski, L.M.Bäcklund, R.Chan, D.T.Jones, and V.P.Collins (2009).
IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas.
  Neuro Oncol, 11, 341-347.  
19935646 L.Dang, D.W.White, S.Gross, B.D.Bennett, M.A.Bittinger, E.M.Driggers, V.R.Fantin, H.G.Jang, S.Jin, M.C.Keenan, K.M.Marks, R.M.Prins, P.S.Ward, K.E.Yen, L.M.Liau, J.D.Rabinowitz, L.C.Cantley, C.B.Thompson, M.G.Vander Heiden, and S.M.Su (2009).
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
  Nature, 462, 739-744.
PDB code: 3inm
19378339 M.R.Kang, M.S.Kim, J.E.Oh, Y.R.Kim, S.Y.Song, S.I.Seo, J.Y.Lee, N.J.Yoo, and S.H.Lee (2009).
Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers.
  Int J Cancer, 125, 353-355.  
19359588 S.Zhao, Y.Lin, W.Xu, W.Jiang, Z.Zha, P.Wang, W.Yu, Z.Li, L.Gong, Y.Peng, J.Ding, Q.Lei, K.L.Guan, and Y.Xiong (2009).
Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.
  Science, 324, 261-265.  
19765000 Y.Sonoda, T.Kumabe, T.Nakamura, R.Saito, M.Kanamori, Y.Yamashita, H.Suzuki, and T.Tominaga (2009).
Analysis of IDH1 and IDH2 mutations in Japanese glioma patients.
  Cancer Sci, 100, 1996-1998.  
18256028 A.B.Taylor, G.Hu, P.J.Hart, and L.McAlister-Henn (2008).
Allosteric motions in structures of yeast NAD+-specific isocitrate dehydrogenase.
  J Biol Chem, 283, 10872-10880.
PDB codes: 3blv 3blw 3blx
18772396 D.W.Parsons, S.Jones, X.Zhang, J.C.Lin, R.J.Leary, P.Angenendt, P.Mankoo, H.Carter, I.M.Siu, G.L.Gallia, A.Olivi, R.McLendon, B.A.Rasheed, S.Keir, T.Nikolskaya, Y.Nikolsky, D.A.Busam, H.Tekleab, L.A.Diaz, J.Hartigan, D.R.Smith, R.L.Strausberg, S.K.Marie, S.M.Shinjo, H.Yan, G.J.Riggins, D.D.Bigner, R.Karchin, N.Papadopoulos, G.Parmigiani, B.Vogelstein, V.E.Velculescu, and K.W.Kinzler (2008).
An integrated genomic analysis of human glioblastoma multiforme.
  Science, 321, 1807-1812.  
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
18058805 M.Starita-Geribaldi, M.Samson, J.M.Guigonis, G.Pointis, and P.Fenichel (2008).
Modified expression of cytoplasmic isocitrate dehydrogenase electrophoretic isoforms in seminal plasma of men with sertoli-cell-only syndrome and seminoma.
  Mol Carcinog, 47, 410-414.  
18275837 Q.Lu, K.I.Minard, and L.McAlister-Henn (2008).
Dual compartmental localization and function of mammalian NADP+-specific isocitrate dehydrogenase in yeast.
  Arch Biochem Biophys, 472, 17-25.  
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
17160675 R.Stokke, D.Madern, A.E.Fedøy, S.Karlsen, N.K.Birkeland, and I.H.Steen (2007).
Biochemical characterization of isocitrate dehydrogenase from Methylococcus capsulatus reveals a unique NAD+-dependent homotetrameric enzyme.
  Arch Microbiol, 187, 361-370.  
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
16759231 M.Karlström, I.H.Steen, D.Madern, A.E.Fedöy, N.K.Birkeland, and R.Ladenstein (2006).
The crystal structure of a hyperthermostable subfamily II isocitrate dehydrogenase from Thermotoga maritima.
  FEBS J, 273, 2851-2868.
PDB code: 1zor
16767773 O.V.Kalinina, and M.S.Gelfand (2006).
Amino acid residues that determine functional specificity of NADP- and NAD-dependent isocitrate and isopropylmalate dehydrogenases.
  Proteins, 64, 1001-1009.  
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.