4umx
IDH1 R132H in complex with cpd 1
Structural highlights
DiseaseIDHC_HUMAN Defects in IDH1 are involved in the development of glioma (GLM) [MIM:137800. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. FunctionPublication Abstract from PubMedCancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) confer a neomorphic enzymatic activity: the reduction of alpha-ketoglutarate (alphaKG) to D-2-hydroxyglutaric acid (2HG), which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. While selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well-understood. A high-throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified Compound 1, a bis-imidazole phenol that inhibits 2HG production in cells. We investigated the mode of inhibition of Compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site, and that inhibition is competitive with respect to Mg2+. A crystal structure of Compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes a direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1, and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme. Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule.,Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, He T, Shi C, Bedel O, McLean LR, Le-Strat F, Zhang Y, Marquette JP, Gao Q, Zhang B, Rak A, Hoffmann D, Rooney E, Vassort A, Englaro W, Li Y, Patel V, Adrian F, Gross S, Wiederschain D, Cheng H, Licht S J Biol Chem. 2014 Nov 12. pii: jbc.M114.608497. PMID:25391653[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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