4JA8

Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor

4JA8 の概要

• エントリーDOI: 10.2210/pdb4ja8/pdb
• 分子名称: Isocitrate dehydrogenase [NADP], mitochondrial, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-[5-(cyclopropylsulfamoyl)-2-thiophen-3-yl-phenyl]-3-[3-(trifluoromethyl)phenyl]urea, ... (6 entities in total)
• 機能のキーワード: protein-inhibitor complex, metabolic enzyme oncometabolite, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion: P48735
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96688.35

構造登録者

Wei, W.,Chen, L.,Wu, M.,Jiang, F.,Travins, J.,Qian, K.,DeLaBarre, B. (登録日: 2013-02-18, 公開日: 2013-04-10, 最終更新日: 2024-02-28)

主引用文献

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, J.O.,Salituro, F.G.,Yan, S.,Murray, S.,Wei, W.,Gao, Y.,Dang, L.,Dorsch, M.,Agresta, S.,Schenkein, D.P.,Biller, S.A.,Su, S.M.,de Botton, S.,Yen, K.E.
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
Science, 340:622-626, 2013

PubMed Abstract: A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and 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 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.

PubMed: 23558173
DOI: 10.1126/science.1234769

実験手法

X-RAY DIFFRACTION (1.55 Å)