1h2n: Difference between revisions

Revision as of 18:20, 2 May 2008

FACTOR INHIBITING HIF-1 ALPHA

OverviewOverview

The activity of the transcription factor hypoxia-inducible factor (HIF) is regulated by oxygen-dependent hydroxylation. Under normoxic conditions, hydroxylation of proline residues triggers destruction of its alpha-subunit while hydroxylation of Asn(803) in the C-terminal transactivation domain of HIF-1 alpha (CAD) prevents its interaction with p300. Here we report crystal structures of the asparagine hydroxylase (factor-inhibiting HIF, FIH) complexed with Fe((II)), 2-oxoglutarate cosubstrate, and CAD fragments, which reveal the structural basis of HIF modification. CAD binding to FIH occurs via an induced fit process at two distinct interaction sites. At the hydroxylation site CAD adopts a loop conformation, contrasting with a helical conformation for the same residues when bound to p300. Asn(803) of CAD is buried and precisely orientated in the active site such that hydroxylation occurs at its beta-carbon. Together with structures with the inhibitors Zn((II)) and N-oxaloylglycine, analysis of the FIH-CAD complexes will assist design of hydroxylase inhibitors with proangiogenic properties. Conserved structural motifs within FIH imply it is one of an extended family of Fe((II)) oxygenases involved in gene regulation.

About this StructureAbout this Structure

1H2N is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha., Elkins JM, Hewitson KS, McNeill LA, Seibel JF, Schlemminger I, Pugh CW, Ratcliffe PJ, Schofield CJ, J Biol Chem. 2003 Jan 17;278(3):1802-6. Epub 2002 Nov 21. PMID:12446723 Page seeded by OCA on Fri May 2 18:20:54 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:1h2n.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 1h2n |SIZE=350|CAPTION= <scene name='initialview01'>1h2n</scene>, resolution 2.84&Aring;
+The line below this paragraph, containing "STRUCTURE_1h2n", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=FEA:So4+Binding+Site+For+Chain+A'>FEA</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=AKG:2-OXYGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</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=
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1h2n|  PDB=1h2n  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h2n OCA], [http://www.ebi.ac.uk/pdbsum/1h2n PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1h2n RCSB]</span>
-}}
 '''FACTOR INHIBITING HIF-1 ALPHA'''
@@ Line 32: / Line 29: @@
 [[Category: Seibel, J F.]]
 [[Category: 2-oxoglutarate]]
-[[Category: asparaginyl hydroxylase]]
+[[Category: Asparaginyl hydroxylase]]
-[[Category: dsbh]]
+[[Category: Dsbh]]
-[[Category: fih]]
+[[Category: Fih]]
-[[Category: hif]]
+[[Category: Hif]]
-[[Category: hydroxylase]]
+[[Category: Hydroxylase]]
-[[Category: hypoxia]]
+[[Category: Hypoxia]]
-[[Category: oxygenase]]
+[[Category: Oxygenase]]
-[[Category: transcription]]
+[[Category: Transcription]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 18:20:54 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:56:29 2008''