8vha
From Proteopedia
Crystal Structure of Human IDH1 R132Q in complex with NADPH and Alpha-Ketoglutarate
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 PubMedMutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.,Mealka M, Sierra NA, Avellaneda Matteo D, Albekioni E, Khoury R, Mai T, Conley BM, Coleman NJ, Sabo KA, Komives EA, Bobkov AA, Cooksy AL, Silletti S, Schiffer JM, Huxford T, Sohl CD Nat Commun. 2024 May 6;15(1):3785. doi: 10.1038/s41467-024-48277-2. PMID:38710674[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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