2YBK

JMJD2A COMPLEXED WITH R-2-HYDROXYGLUTARATE

Summary for 2YBK

• Entry DOI: 10.2210/pdb2ybk/pdb
• Related: 2GF7 2GFA 2GP3 2GP5 2VD7 2WWJ 2YBP 2YBS
• Descriptor: LYSINE-SPECIFIC DEMETHYLASE 4A, NICKEL (II) ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: oxidoreductase, non-heme, iron, 2-oxoglutarate, dioxygenase, oxygenase, double-stranded beta helix, dsbh, facial triad, metal binding protein, epigenetic and transcription regulation, chromatin regulator, hydroxylation
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 89232.43

Authors

Chowdhury, R.,McDonough, M.A.,Schofield, C.J. (deposition date: 2011-03-08, release date: 2011-04-06, Last modification date: 2023-12-20)

Primary citation

Chowdhury, R.,Yeoh, K.K.,Tian, Y.M.,Hillringhaus, L.,Bagg, E.A.,Rose, N.R.,Leung, I.K.,Li, X.S.,Woon, E.C.,Yang, M.,McDonough, M.A.,King, O.N.,Clifton, I.J.,Klose, R.J.,Claridge, T.D.,Ratcliffe, P.J.,Schofield, C.J.,Kawamura, A.
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
EMBO Rep., 12:463-469, 2011

PubMed Abstract: Mutations in isocitrate dehydrogenases (IDHs) have a gain-of-function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R- and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.

PubMed: 21460794
DOI: 10.1038/embor.2011.43

Experimental method

X-RAY DIFFRACTION (2.4 Å)