PDBsum entry 3mas

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Oxidoreductase PDB id
Jmol PyMol
Protein chain
393 a.a. *
NAP ×2
ICT ×2
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of heterodimeric r132h mutant of human cyt NADP(+)-dependent isocitrate dehydrogenase in complex with isocitrate
Structure: Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: a. Synonym: idh, cytosolic NADP-isocitrate dehydrogenase, oxal decarboxylase, NADP(+)-specific icdh, idp. Engineered: yes. Mutation: yes. Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: b. Synonym: idh, cytosolic NADP-isocitrate dehydrogenase, oxal
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: idh1, picd. Expressed in: escherichia coli. Expression_system_taxid: 562.
3.20Å     R-factor:   0.235     R-free:   0.283
Authors: B.Yang,Y.Peng,J.Ding
Key ref: B.Yang et al. (2010). Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H. Cell Res, 20, 1188-1200. PubMed id: 20975740
24-Mar-10     Release date:   10-Nov-10    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O75874  (IDHC_HUMAN) -  Isocitrate dehydrogenase [NADP] cytoplasmic
414 a.a.
393 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.  - Isocitrate dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
Bound ligand (Het Group name = ICT)
corresponds exactly
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     extracellular region   10 terms 
  Biological process     regulation of phospholipid biosynthetic process   14 terms 
  Biochemical function     oxidoreductase activity     12 terms  


Cell Res 20:1188-1200 (2010)
PubMed id: 20975740  
Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.
B.Yang, C.Zhong, Y.Peng, Z.Lai, J.Ding.
Human cytosolic NADP-IDH (IDH1) has recently been found to be involved in tumorigenesis. Notably, the tumor-derived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting α-ketoglutarate (αKG) to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate (ICT) bound. The structural data together with mutagenesis and biochemical data reveal a previously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT-binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conformation, therefore shedding light on the molecular mechanism of the "off switch" of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained αKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of αKG during the transfer of a hydride anion from NADPH to αKG, which provides new insights into the mechanism of the "on switch" of the hypothetically oncogenic reduction activity of IDH1 by this mutation.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21079649 S.Zhao, and K.L.Guan (2010).
IDH1 mutant structures reveal a mechanism of dominant inhibition.
  Cell Res, 20, 1279-1281.  
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