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PDBsum entry 3inm

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
3inm
Jmol
Contents
Protein chain
407 a.a. *
Ligands
NDP ×3
AKG ×3
GOL ×3
Metals
_NA ×3
_CA ×3
Waters ×301
* Residue conservation analysis
PDB id:
3inm
Name: Oxidoreductase
Title: Crystal structure of human cytosolic NADP(+)-dependent isoci dehydrogenase r132h mutant in complex with NADPH, alpha-ket and calcium(2+)
Structure: Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: a, b, c. Synonym: idh, cytosolic NADP-isocitrate dehydrogenase, oxal decarboxylase, NADP(+)-specific icdh, idp. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: idh1, picd. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.10Å     R-factor:   0.222     R-free:   0.262
Authors: E.Fontano,R.S.Brown,R.K.Suto,B.Bhyravbhatla
Key ref:
L.Dang et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 462, 739-744. PubMed id: 19935646 DOI: 10.1038/nature08617
Date:
12-Aug-09     Release date:   24-Nov-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O75874  (IDHC_HUMAN) -  Isocitrate dehydrogenase [NADP] cytoplasmic
Seq:
Struc:
414 a.a.
407 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.42  - Isocitrate dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
Isocitrate
+
NADP(+)
Bound ligand (Het Group name = NDP)
corresponds exactly
=
2-oxoglutarate
Bound ligand (Het Group name = AKG)
corresponds exactly
+ CO(2)
+ NADPH
      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  

 

 
    reference    
 
 
DOI no: 10.1038/nature08617 Nature 462:739-744 (2009)
PubMed id: 19935646  
 
 
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
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, S.M.Su.
 
  ABSTRACT  
 
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
 
  Selected figure(s)  
 
Figure 3.
Figure 3: Structural analysis of R132H mutant IDH1. a, On the left is shown an overlay of R132H mutant IDH1 (green) and wild-type IDH1 (grey) structures in the ‘closed’ conformation. On the right is shown an overlay of wild-type IDH1 (blue) structure in the ‘open’ conformation with mutant IDH1 (green) for comparison. b, Close-up comparison of the R132H IDH1 active site (left) with α-ketoglutarate (yellow) and NADPH (grey) and the wild-type IDH1 active site (right) with isocitrate (yellow) and NADP (grey). Residues coming from the other monomer are denoted with a prime (′) symbol. In addition to the mutation at residue 132, the major changes are the positions of the catalytic residues Tyr 139 and Lys 212′. c, Wall-eyed stereo image showing the composite omit map for α-ketoglutarate, NADPH, calcium ion, His 132 and other key catalytic residues in the R132H mutant active site contoured at the 1σ level.
Figure 4.
Figure 4: Human malignant gliomas containing R132 mutations in IDH1 contain increased concentrations of 2HG. Human glioma samples obtained by surgical resection were snap frozen, genotyped to stratify as wild type (n = 10) or carrying an R132 mutant allele (mutant) (n = 12) and metabolites extracted for LC–MS analysis. Among the 12 mutant tumours, 10 carried a R132H mutation, one an R132S mutation, and one an R132G mutation. Each symbol represents the amount of the listed metabolite found in each tumour sample. Horizontal lines indicate the group sample means. The difference in 2HG observed between wild-type and R132 mutant IDH1 tumours was statistically significant by Student’s t-test (P < 0.0001). There were no statistically significant differences in α-ketoglutarate, malate, fumarate, succinate, or isocitrate levels between the wild-type and R132 mutant IDH1 tumours.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2009, 462, 739-744) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22898539 A.H.Shih, O.Abdel-Wahab, J.P.Patel, and R.L.Levine (2012).
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IDH mutation impairs histone demethylation and results in a block to cell differentiation.
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23001348 D.C.Wallace (2012).
Mitochondria and cancer.
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Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.
  Nature, 482, 226-231.  
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IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics.
  Nature, 488, 656-659.  
22343896 P.Koivunen, S.Lee, C.G.Duncan, G.Lopez, G.Lu, S.Ramkissoon, J.A.Losman, P.Joensuu, U.Bergmann, S.Gross, J.Travins, S.Weiss, R.Looper, K.L.Ligon, R.G.Verhaak, H.Yan, and W.G.Kaelin (2012).
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.
  Nature, 483, 484-488.  
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IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.
  Nature, 483, 479-483.  
21473982 A.Erez, O.A.Shchelochkov, S.E.Plon, F.Scaglia, and B.Lee (2011).
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21383721 A.Farrell (2011).
A close look at cancer.
  Nat Med, 17, 262-265.  
21415854 A.Schulze (2011).
A fresh look at cancer metabolism in a historical setting.
  EMBO Rep, 12, 289-291.  
21242296 A.Wolf, S.Agnihotri, J.Micallef, J.Mukherjee, N.Sabha, R.Cairns, C.Hawkins, and A.Guha (2011).
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21129061 A.von Deimling, A.Korshunov, and C.Hartmann (2011).
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21301796 C.Frezza, P.J.Pollard, and E.Gottlieb (2011).
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21225914 D.Rakheja, M.Mitui, R.L.Boriack, and R.J.DeBerardinis (2011).
Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors.
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21080253 D.Rakheja, R.L.Boriack, M.Mitui, S.Khokhar, S.A.Holt, and P.Kapur (2011).
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21054626 E.E.Bar (2011).
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  Brain Pathol, 21, 119-129.  
20816705 E.F.Mason, and J.C.Rathmell (2011).
Cell metabolism: an essential link between cell growth and apoptosis.
  Biochim Biophys Acta, 1813, 645-654.  
21554053 F.Ducray, A.Idbaih, X.W.Wang, C.Cheneau, M.Labussiere, and M.Sanson (2011).
Predictive and prognostic factors for gliomas.
  Expert Rev Anticancer Ther, 11, 781-789.  
21326614 G.Jin, Z.J.Reitman, I.Spasojevic, I.Batinic-Haberle, J.Yang, O.Schmidt-Kittler, D.D.Bigner, and H.Yan (2011).
2-Hydroxyglutarate Production, but Not Dominant Negative Function, Is Conferred by Glioma-Derived NADP-Dependent Isocitrate Dehydrogenase Mutations.
  PLoS One, 6, e16812.  
20849810 G.Solaini, G.Sgarbi, and A.Baracca (2011).
Oxidative phosphorylation in cancer cells.
  Biochim Biophys Acta, 1807, 534-542.  
20473936 G.Toedt, S.Barbus, M.Wolter, J.Felsberg, B.Tews, F.Blond, M.C.Sabel, S.Hofmann, N.Becker, C.Hartmann, H.Ohgaki, A.von Deimling, O.D.Wiestler, M.Hahn, P.Lichter, G.Reifenberger, and B.Radlwimmer (2011).
Molecular signatures classify astrocytic gliomas by IDH1 mutation status.
  Int J Cancer, 128, 1095-1103.  
20629098 H.M.Lin, N.A.Helsby, D.D.Rowan, and L.R.Ferguson (2011).
Using metabolomic analysis to understand inflammatory bowel diseases.
  Inflamm Bowel Dis, 17, 1021-1029.  
20725730 I.F.Pollack, R.L.Hamilton, R.W.Sobol, M.N.Nikiforova, M.A.Lyons-Weiler, W.A.Laframboise, P.C.Burger, D.J.Brat, M.K.Rosenblum, E.J.Holmes, T.Zhou, and R.I.Jakacki (2011).
IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group.
  Childs Nerv Syst, 27, 87-94.  
21386834 I.J.Majewski, and R.Bernards (2011).
Taming the dragon: genomic biomarkers to individualize the treatment of cancer.
  Nat Med, 17, 304-312.  
  21403835 J.Kurhanewicz, D.B.Vigneron, K.Brindle, E.Y.Chekmenev, A.Comment, C.H.Cunningham, R.J.Deberardinis, G.G.Green, M.O.Leach, S.S.Rajan, R.R.Rizi, B.D.Ross, W.S.Warren, and C.R.Malloy (2011).
Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research.
  Neoplasia, 13, 81-97.  
21383741 J.R.Prensner, and A.M.Chinnaiyan (2011).
Metabolism unhinged: IDH mutations in cancer.
  Nat Med, 17, 291-293.  
20962861 K.Yoshida, M.Sanada, M.Kato, R.Kawahata, A.Matsubara, J.Takita, L.Y.Shih, H.Mori, H.P.Koeffler, and S.Ogawa (2011).
A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders.
  Leukemia, 25, 184-186.  
22057236 M.F.Amary, S.Damato, D.Halai, M.Eskandarpour, F.Berisha, F.Bonar, S.McCarthy, V.R.Fantin, K.S.Straley, S.Lobo, W.Aston, C.L.Green, R.E.Gale, R.Tirabosco, A.Futreal, P.Campbell, N.Presneau, and A.M.Flanagan (2011).
Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.
  Nat Genet, 43, 1262-1265.  
21878982 M.G.Vander Heiden (2011).
Targeting cancer metabolism: a therapeutic window opens.
  Nat Rev Drug Discov, 10, 671-684.  
21352804 M.K.Kaneko, W.Tian, S.Takano, H.Suzuki, Y.Sawa, Y.Hozumi, K.Goto, K.Yamazaki, C.Kitanaka, and Y.Kato (2011).
Establishment of a novel monoclonal antibody SMab-1 specific for IDH1-R132S mutation.
  Biochem Biophys Res Commun, 406, 608-613.  
21250968 M.M.Pichler, C.Bodner, C.Fischer, A.J.Deutsch, K.Hiden, C.Beham-Schmid, W.Linkesch, C.Guelly, H.Sill, and A.Wölfler (2011).
Evaluation of mutations in the isocitrate dehydrogenase genes in therapy-related and secondary acute myeloid leukaemia identifies a patient with clonal evolution to IDH2 R172K homozygosity due to uniparental disomy.
  Br J Haematol, 152, 669-672.  
20615753 N.K.Kloosterhof, L.B.Bralten, H.J.Dubbink, P.J.French, and M.J.van den Bent (2011).
Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?
  Lancet Oncol, 12, 83-91.  
21258394 R.A.Cairns, I.S.Harris, and T.W.Mak (2011).
Regulation of cancer cell metabolism.
  Nat Rev Cancer, 11, 85-95.  
21460794 R.Chowdhury, K.K.Yeoh, Y.M.Tian, L.Hillringhaus, E.A.Bagg, N.R.Rose, I.K.Leung, X.S.Li, E.C.Woon, M.Yang, M.A.McDonough, O.N.King, I.J.Clifton, R.J.Klose, T.D.Claridge, P.J.Ratcliffe, C.J.Schofield, and A.Kawamura (2011).
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
  EMBO Rep, 12, 463-469.
PDB codes: 2ybk 2ybp 2ybs 2yc0 2yde
20820872 R.Ferrer-Luna, L.Núñez, J.Piquer, E.Arias, F.Dasí, A.Cervio, N.Arakaki, G.Sevlever, B.Celda, and H.Martinetto (2011).
Whole-genomic survey of oligodendroglial tumors: correlation between allelic imbalances and gene expression profiles.
  J Neurooncol, 103, 71-85.  
20727073 S.Brehmer, S.Pusch, K.Schmieder, A.von Deimling, and C.Hartmann (2011).
Mutational analysis of D2HGDH and L2HGDH in brain tumours without IDH1 or IDH2 mutations.
  Neuropathol Appl Neurobiol, 37, 330-332.  
21181477 S.C.Williams, M.A.Karajannis, L.Chiriboga, J.G.Golfinos, A.von Deimling, and D.Zagzag (2011).
R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma.
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20962862 S.Soverini, J.Score, I.Iacobucci, A.Poerio, A.Lonetti, A.Gnani, S.Colarossi, A.Ferrari, F.Castagnetti, G.Rosti, F.Cervantes, A.Hochhaus, M.Delledonne, A.Ferrarini, M.Sazzini, D.Luiselli, M.Baccarani, N.C.Cross, and G.Martinelli (2011).
IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis.
  Leukemia, 25, 178-181.  
21344322 S.Takano, W.Tian, M.Matsuda, T.Yamamoto, E.Ishikawa, M.K.Kaneko, K.Yamazaki, Y.Kato, and A.Matsumura (2011).
Detection of IDH1 mutation in human gliomas: comparison of immunohistochemistry and sequencing.
  Brain Tumor Pathol, 28, 115-123.  
22057234 T.C.Pansuriya, R.van Eijk, P.d'Adamo, M.A.van Ruler, M.L.Kuijjer, J.Oosting, A.M.Cleton-Jansen, J.G.van Oosterwijk, S.L.Verbeke, D.Meijer, T.van Wezel, K.H.Nord, L.Sangiorgi, B.Toker, B.Liegl-Atzwanger, M.San-Julian, R.Sciot, N.Limaye, L.G.Kindblom, S.Daugaard, C.Godfraind, L.M.Boon, M.Vikkula, K.C.Kurek, K.Szuhai, P.J.French, and J.V.Bovée (2011).
Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.
  Nat Genet, 43, 1256-1261.  
  21356389 T.Shibata, A.Kokubu, M.Miyamoto, Y.Sasajima, and N.Yamazaki (2011).
Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation.
  Am J Pathol, 178, 1395-1402.  
21079611 W.C.Chou, W.C.Lei, B.S.Ko, H.A.Hou, C.Y.Chen, J.L.Tang, M.Yao, W.Tsay, S.J.Wu, S.Y.Huang, S.C.Hsu, Y.C.Chen, Y.C.Chang, K.T.Kuo, F.Y.Lee, M.C.Liu, C.W.Liu, M.H.Tseng, C.F.Huang, and H.F.Tien (2011).
The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia.
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21508971 W.H.Koppenol, P.L.Bounds, and C.V.Dang (2011).
Otto Warburg's contributions to current concepts of cancer metabolism.
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Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.
  Proc Natl Acad Sci U S A, 108, 3270-3275.  
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Where metabolism meets oncogenesis: another false lead?
  Lancet Oncol, 11, 309-310.  
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Hypoxia-inducible factors and the response to hypoxic stress.
  Mol Cell, 40, 294-309.  
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.
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20428194 A.Tefferi (2010).
Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.
  Leukemia, 24, 1128-1138.  
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IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.
  Leukemia, 24, 1302-1309.  
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.
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PDB codes: 3map 3mar 3mas
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