6adg

Crystal Structures of IDH1 R132H in complex with AG-881

spinqualitylabelsall models 6adg, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6adg is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: 9UO, MG, NDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease IDHC_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. Function IDHC_HUMAN Publication Abstract from PubMed Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2.,Ma R, Yun CH Biochem Biophys Res Commun. 2018 Aug 18. pii: S0006-291X(18)31750-9. doi:, 10.1016/j.bbrc.2018.08.068. PMID:30131249 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Isocitrate dehydrogenase 3D structures

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