2CGN

FACTOR INHIBITING HIF-1 ALPHA with succinate

Summary for 2CGN

• Entry DOI: 10.2210/pdb2cgn/pdb
• Related: 1H2K 1H2L 1H2M 1H2N 1IZ3 1MZE 1MZF 1YCI 2CGO
• Descriptor: HYPOXIA-INDUCIBLE FACTOR 1 ALPHA INHIBITOR, FE (III) ION, SUCCINIC ACID, ... (5 entities in total)
• Functional Keywords: 2-oxoglutarate, acetylation, activator, oxidoreductase, alternative splicing, asparaginyl hydroxylase, dna-binding, dsbh, fi, hif, hydroxylation, hypoxia, nuclear protein, oxygenase, phosphorylation, polymorphism, s-nitrosylation, transcription, transcription activator/inhibitor, transcription regulation
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: Q9NWT6
• Total number of polymer chains: 1
• Total formula weight: 40886.47

Authors

McDonough, M.A.,Clifton, I.J.,Schofield, C.J. (deposition date: 2006-03-09, release date: 2006-12-13, Last modification date: 2023-12-13)

Primary citation

Hewitson, K.,Lienard, B.,McDonough, M.A.,Clifton, I.J.,Butler, D.,Soares, A.S.,Oldham, N.J.,McNeill, L.A.,Schofield, C.J.
Structural and Mechanistic Studies on the Inhibition of the Hypoxia-Inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates.
J.Biol.Chem., 282:3293-3301, 2007

PubMed Abstract: In humans both the levels and activity of the alpha-subunit of the hypoxia-inducible transcription factor (HIF-alpha) are regulated by its post-translation hydroxylation as catalyzed by iron- and 2-oxoglutarate (2OG)-dependent prolyl and asparaginyl hydroxylases (PHD1-3 and factor-inhibiting HIF (FIH), respectively). One consequence of hypoxia is the accumulation of tricarboxylic acid cycle intermediates (TCAIs). In vitro assays were used to assess non-2OG TCAIs as inhibitors of purified PHD2 and FIH. Under the assay conditions, no significant FIH inhibition was observed by the TCAIs or pyruvate, but fumarate, succinate, and isocitrate inhibited PHD2. Mass spectrometric analyses under nondenaturing conditions were used to investigate the binding of TCAIs to PHD2 and supported the solution studies. X-ray crystal structures of FIH in complex with Fe(II) and fumarate or succinate revealed similar binding modes for each in the 2OG co-substrate binding site. The in vitro results suggest that the cellular inhibition of PHD2, but probably not FIH, by fumarate and succinate may play a role in the Warburg effect providing that appropriate relative concentrations of the components are achieved under physiological conditions.

PubMed: 17135241
DOI: 10.1074/JBC.M608337200

Experimental method

X-RAY DIFFRACTION (2.4 Å)