3INM

Crystal structure of human cytosolic NADP(+)-dependent isocitrate dehydrogenase R132H mutant in complex with NADPH, ALPHA-KETOGLUTARATE and CALCIUM(2+)

Summary for 3INM

• Entry DOI: 10.2210/pdb3inm/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-OXOGLUTARIC ACID, ... (7 entities in total)
• Functional Keywords: rossmann fold, nadp, ketoglutarate, quaternary complex, oxidoreductase, glyoxylate bypass, magnesium, manganese, metal-binding, peroxisome, tricarboxylic acid cycle
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : O75874
• Total number of polymer chains: 3
• Total formula weight: 147547.10

Authors

Fontano, E.,Brown, R.S.,Suto, R.K.,Bhyravbhatla, B. (deposition date: 2009-08-12, release date: 2009-11-24, Last modification date: 2023-09-06)

Primary citation

Dang, L.,White, D.W.,Gross, S.,Bennett, B.D.,Bittinger, M.A.,Driggers, E.M.,Fantin, V.R.,Jang, H.G.,Jin, S.,Keenan, M.C.,Marks, K.M.,Prins, R.M.,Ward, P.S.,Yen, K.E.,Liau, L.M.,Rabinowitz, J.D.,Cantley, L.C.,Thompson, C.B.,Vander Heiden, M.G.,Su, S.M.
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
Nature, 462:739-744, 2009

PubMed 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.

PubMed: 19935646
DOI: 10.1038/nature08617

Experimental method

X-RAY DIFFRACTION (2.1 Å)