2ilm

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[[Image:2ilm.jpg|left|200px]]
 
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{{Structure
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==Factor Inhibiting HIF-1 Alpha D201A Mutant in Complex with FE(II), Alpha-Ketoglutarate and HIF-1 Alpha 35mer==
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|PDB= 2ilm |SIZE=350|CAPTION= <scene name='initialview01'>2ilm</scene>, resolution 2.30&Aring;
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<StructureSection load='2ilm' size='340' side='right'caption='[[2ilm]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=AKG:2-OXYGLUTARIC+ACID'>AKG</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
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<table><tr><td colspan='2'>[[2ilm]] 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=2ILM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ILM FirstGlance]. <br>
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|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]
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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]] 2.3&#8491;</td></tr>
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|GENE= HIF1AN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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}}
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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=2ilm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ilm OCA], [https://pdbe.org/2ilm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ilm RCSB], [https://www.ebi.ac.uk/pdbsum/2ilm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ilm 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/il/2ilm_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=2ilm 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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A 2-His-1-carboxylate triad of iron binding residues is present in many non-heme iron oxygenases including the Fe(II) and 2-oxoglutarate (2OG)-dependent dioxygenases. Three variants (D201A, D201E, and D201G) of the iron binding Asp-201 residue of an asparaginyl hydroxylase, factor inhibiting HIF (FIH), were made and analyzed. FIH-D201A and FIH-D201E did not catalyze asparaginyl hydroxylation, but in the presence of a reducing agent, they displayed enhanced 2OG turnover when compared with wild-type FIH. Turnover of 2OG by FIH-D201A was significantly stimulated by the addition of HIF-1alpha(786-826) peptide. Like FIH-D201A and D201E, the D201G variant enhanced 2OG turnover but rather unexpectedly catalyzed asparaginyl hydroxylation. Crystal structures of the FIH-D201A and D201G variants in complex with Fe(II)/Zn(II), 2OG, and HIF-1alpha(786-826/788-806) implied that only two FIH-based residues (His-199 and His-279) are required for metal binding. The results indicate that variation of 2OG-dependent dioxygenase iron-ligating residues as a means of functional assignment should be treated with caution. The results are of mechanistic interest in the light of recent biochemical and structural analyses of non-heme iron and 2OG-dependent halogenases that are similar to the FIH-D201A/G variants in that they use only two His-residues to ligate iron.
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'''Factor Inhibiting HIF-1 Alpha D201A Mutant in Complex with FE(II), Alpha-Ketoglutarate and HIF-1 Alpha 35mer'''
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Evidence that two enzyme-derived histidine ligands are sufficient for iron binding and catalysis by factor inhibiting HIF (FIH).,Hewitson KS, Holmes SL, Ehrismann D, Hardy AP, Chowdhury R, Schofield CJ, McDonough MA J Biol Chem. 2008 Sep 19;283(38):25971-8. Epub 2008 Jul 8. PMID:18611856<ref>PMID:18611856</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2ilm" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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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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*[[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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==About this Structure==
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*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
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2ILM is a [[Protein complex]] structure of sequences 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=2ILM OCA].
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== References ==
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<references/>
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==Reference==
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__TOC__
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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://www.ncbi.nlm.nih.gov/pubmed/12446723 12446723]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Peptide-aspartate beta-dioxygenase]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Mcdonough MA]]
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[[Category: Mcdonough, M A.]]
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[[Category: Schofield CJ]]
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[[Category: Schofield, C J.]]
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[[Category: AKG]]
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[[Category: BCT]]
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[[Category: FE2]]
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[[Category: GOL]]
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[[Category: SO4]]
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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: inhibitor 2-oxoglutarate]]
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[[Category: oxidoreductase]]
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[[Category: oxygenase]]
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[[Category: transcription]]
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[[Category: transcription regulator]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:30:52 2008''
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Current revision

Factor Inhibiting HIF-1 Alpha D201A Mutant in Complex with FE(II), Alpha-Ketoglutarate and HIF-1 Alpha 35mer

PDB ID 2ilm

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