2YDE

FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH S-2-HYDROXYGLUTARATE

Summary for 2YDE

• Entry DOI: 10.2210/pdb2yde/pdb
• Related: 1H2K 1H2L 1H2M 1H2N 1IZ3 1MZE 1MZF 1YCI 2CGN 2CGO 2W0X 2WA3 2WA4 2XUM 2Y0I 2YC0
• Descriptor: HYPOXIA-INDUCIBLE FACTOR 1-ALPHA INHIBITOR, FE (III) ION, (2S)-2-HYDROXYPENTANEDIOIC ACID, ... (6 entities in total)
• Functional Keywords: oxidoreductase, non-heme iron, dioxygenase, metal-binding, transcription, helix-loop-helix-beta, dsbh, facial triad, asparaginyl/ aspartyl hydroxylase, ankyrin repeat domain, ard, beta-hydroxylation, transcription activator/inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 41531.06

Authors

Chowdhury, R.,Clifton, I.J.,Schofield, C.J. (deposition date: 2011-03-18, release date: 2011-03-30, 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 (2.28 Å)