1h2k

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[[Image:1h2k.gif|left|200px]]<br />
 
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<applet load="1h2k" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1h2k, resolution 2.15&Aring;" />
 
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'''FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH HIF-1 ALPHA FRAGMENT PEPTIDE'''<br />
 
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==Overview==
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==Factor Inhibiting HIF-1 alpha in complex with HIF-1 alpha fragment peptide==
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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.
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<StructureSection load='1h2k' size='340' side='right'caption='[[1h2k]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1h2k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H2K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H2K FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1h2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h2k OCA], [https://pdbe.org/1h2k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h2k RCSB], [https://www.ebi.ac.uk/pdbsum/1h2k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h2k ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/HIF1N_HUMAN HIF1N_HUMAN] Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.<ref>PMID:12080085</ref> <ref>PMID:12042299</ref> <ref>PMID:17003112</ref> <ref>PMID:18299578</ref> <ref>PMID:19245366</ref> <ref>PMID:17573339</ref> <ref>PMID:21251231</ref> <ref>PMID:21177872</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h2/1h2k_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h2k ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:12446723</ref>
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1H2K is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FE2, SO4 and OGA as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: FE1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H2K OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12446723 12446723]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1h2k" style="background-color:#fffaf0;"></div>
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[[Category: Protein complex]]
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[[Category: Elkins, J.M.]]
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[[Category: Hewitson, K.S.]]
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[[Category: Mcneill, L.A.]]
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[[Category: Schlemminger, I.]]
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[[Category: Schofield, C.J.]]
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[[Category: Seibel, J.F.]]
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[[Category: FE2]]
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[[Category: OGA]]
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[[Category: SO4]]
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[[Category: 2-oxoglutarate]]
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[[Category: asparaginyl hydroxylase]]
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[[Category: dsbh]]
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[[Category: fih]]
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[[Category: hif]]
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[[Category: hypoxia]]
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[[Category: oxygenase]]
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[[Category: phosphorylation]]
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[[Category: transcription]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:12:03 2007''
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==See Also==
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*[[Factor inhibiting HIF|Factor inhibiting HIF]]
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*[[Hypoxia-Inducible factor 1 alpha inhibitor|Hypoxia-Inducible factor 1 alpha inhibitor]]
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*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Elkins JM]]
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[[Category: Hewitson KS]]
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[[Category: McNeill LA]]
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[[Category: Schlemminger I]]
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[[Category: Schofield CJ]]
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[[Category: Seibel JF]]

Current revision

Factor Inhibiting HIF-1 alpha in complex with HIF-1 alpha fragment peptide

PDB ID 1h2k

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