3PUQ

CEKDM7A from C.Elegans, complex with alpha-KG

Summary for 3PUQ

• Entry DOI: 10.2210/pdb3puq/pdb
• Related: 3PUR
• Descriptor: Lysine-specific demethylase 7 homolog, FE (II) ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: demethylase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Caenorhabditis elegans (nematode)
• Cellular location: Nucleus: Q9GYI0
• Total number of polymer chains: 2
• Total formula weight: 124740.70

Authors

Yang, Y.,Wang, P.,Xu, W.,Xu, Y. (deposition date: 2010-12-06, release date: 2011-01-26, Last modification date: 2024-03-20)

Primary citation

Xu, W.,Yang, H.,Liu, Y.,Yang, Y.,Wang, P.,Kim, S.-H.,Ito, S.,Yang, C.,Wang, P.,Xiao, M.-T.,Liu, L.-X.,Jiang, W.-Q.,Liu, J.,Zhang, J.-Y.,Wang, B.,Frye, S.,Zhang, Y.,Xu, Y.-H.,Lei, Q.-Y.,Guan, K.-L.,Zhao, S.-M.,Xiong, Y.
Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases
Cancer Cell, 19:17-30, 2011

PubMed Abstract: IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

PubMed: 21251613
DOI: 10.1016/j.ccr.2010.12.014

Experimental method

X-RAY DIFFRACTION (2.25 Å)