4I3L

Crystal structure of a metabolic reductase with 6-benzyl-1-hydroxy-4-methylpyridin-2(1H)-one

Summary for 4I3L

• Entry DOI: 10.2210/pdb4i3l/pdb
• Related: 3MAP
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: isocitrate dehydrogenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O75874
• Total number of polymer chains: 2
• Total formula weight: 95300.57

Authors

Zheng, B.,Yao, Y.,Liu, Z.,Deng, L.,Anglin, J.L.,Jiang, H.,Prasad, B.V.V.,Song, Y. (deposition date: 2012-11-26, release date: 2013-05-22, Last modification date: 2024-02-28)

Primary citation

Zheng, B.,Yao, Y.,Liu, Z.,Deng, L.,Anglin, J.L.,Jiang, H.,Prasad, B.V.,Song, Y.
Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase.
ACS Med Chem Lett, 4:542-546, 2013

PubMed Abstract: Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in ~75% glioma and ~20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of α-ketoglutaric acid to -2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with K values as low as 120 nM. These compounds exhibit >60-fold selectivity against wild-type IDH1 and can inhibit the production of -2-hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds.

PubMed: 23795241
DOI: 10.1021/ml400036z

Experimental method

X-RAY DIFFRACTION (3.292 Å)