6q6f

Crystal structure of IDH1 R132H in complex with HMS101

spinqualitylabelsall models 6q6f, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6q6f is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HJQ Gene: IDH1, PICD (HUMAN) Activity: Isocitrate dehydrogenase (NADP(+)), with EC number 1.1.1.42 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. Publication Abstract from PubMed Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models. In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site.,Chaturvedi A, Goparaju R, Gupta C, Weder J, Klunemann T, Araujo Cruz MM, Kloos A, Goerlich K, Schottmann R, Othman B, Struys EA, Bahre H, Grote-Koska D, Brand K, Ganser A, Preller M, Heuser M Leukemia. 2019 Oct 4. pii: 10.1038/s41375-019-0582-x. doi:, 10.1038/s41375-019-0582-x. PMID:31586149 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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