2cgo: Difference between revisions

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Revision as of 17:15, 20 March 2008

File:2cgo.jpg

, resolution 2.30Å

Sites:

Ligands:

, and

Activity:

Peptide-aspartate beta-dioxygenase, with EC number 1.14.11.16

Coordinates:

save as pdb, mmCIF, xml

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 Thu Mar 20 16:15:09 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:2cgo.jpg|left|200px]]<br /><applet load="2cgo" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2cgo.jpg|left|200px]]
-caption="2cgo, resolution 2.30&Aring;" />
-'''FACTOR INHIBITING HIF-1 ALPHA WITH FUMARATE'''<br />
+ {{Structure
+|PDB= 2cgo |SIZE=350|CAPTION= <scene name='initialview01'>2cgo</scene>, resolution 2.30&Aring;
+|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>
+|LIGAND= <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=FMR:FUMARATE'>FMR</scene>
+|ACTIVITY= [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]
+|GENE=
+}}
+'''FACTOR INHIBITING HIF-1 ALPHA WITH FUMARATE'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-CGO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FE:'>FE</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=FMR:'>FMR</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CGO OCA].
+CGO is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CGO OCA].
 ==Reference==
-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17135241 17135241]
+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:[http://www.ncbi.nlm.nih.gov/pubmed/17135241 17135241]
 [[Category: Homo sapiens]]
 [[Category: Peptide-aspartate beta-dioxygenase]]
@@ Line 44: / Line 53: @@
 [[Category: transcription regulation]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:48:25 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:15:09 2008''