2cgo: Difference between revisions

Revision as of 22:05, 3 May 2008

FACTOR INHIBITING HIF-1 ALPHA WITH FUMARATE

OverviewOverview

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.

About this StructureAbout this Structure

2CGO is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates., Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS, Oldham NJ, McNeill LA, Schofield CJ, J Biol Chem. 2007 Feb 2;282(5):3293-301. Epub 2006 Nov 29. PMID:17135241 Page seeded by OCA on Sat May 3 22:05:51 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 [[Image:2cgo.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2cgo |SIZE=350|CAPTION= <scene name='initialview01'>2cgo</scene>, resolution 2.30&Aring;
+The line below this paragraph, containing "STRUCTURE_2cgo", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=FMR:FUMARATE'>FMR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptide-aspartate_beta-dioxygenase Peptide-aspartate beta-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.16 1.14.11.16] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_2cgo|  PDB=2cgo  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2cgo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cgo OCA], [http://www.ebi.ac.uk/pdbsum/2cgo PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2cgo RCSB]</span>
-}}
 '''FACTOR INHIBITING HIF-1 ALPHA WITH FUMARATE'''
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 [[Category: Schofield, C J.]]
 [[Category: 2-oxoglutarate]]
-[[Category: acetylation]]
+[[Category: Acetylation]]
-[[Category: activator]]
+[[Category: Activator]]
-[[Category: alternative splicing]]
+[[Category: Alternative splicing]]
-[[Category: asparaginyl hydroxylase]]
+[[Category: Asparaginyl hydroxylase]]
-[[Category: dioxygenase]]
+[[Category: Dioxygenase]]
-[[Category: dna-binding]]
+[[Category: Dna-binding]]
-[[Category: dsbh]]
+[[Category: Dsbh]]
-[[Category: fi]]
+[[Category: Fi]]
-[[Category: hif]]
+[[Category: Hif]]
-[[Category: hydroxylation]]
+[[Category: Hydroxylation]]
-[[Category: hypoxia]]
+[[Category: Hypoxia]]
-[[Category: iron]]
+[[Category: Iron]]
-[[Category: metal-binding]]
+[[Category: Metal-binding]]
-[[Category: nuclear protein]]
+[[Category: Nuclear protein]]
-[[Category: oxidoreductase]]
+[[Category: Oxidoreductase]]
-[[Category: oxygenase]]
+[[Category: Oxygenase]]
-[[Category: phosphorylation]]
+[[Category: Phosphorylation]]
-[[Category: polymorphism]]
+[[Category: Polymorphism]]
-[[Category: s-nitrosylation]]
+[[Category: S-nitrosylation]]
-[[Category: transcription]]
+[[Category: Transcription]]
-[[Category: transcription activator/inhibitor]]
+[[Category: Transcription activator/inhibitor]]
-[[Category: transcription regulation]]
+[[Category: Transcription regulation]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 22:05:51 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:21:10 2008''