4ja8 | pdb_00004ja8
Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor
Structural highlights
Disease[IDHP_HUMAN] D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:613657]. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.[1] Function[IDHP_HUMAN] Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex. Publication Abstract from PubMedA number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases- 1 and -2 (IDH1, IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite R (-)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia (AML) cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer. Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation.,Wang F, Travins J, Delabarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE Science. 2013 Apr 4. PMID:23558173[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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