4gs9

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==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist==
==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist==
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<StructureSection load='4gs9' size='340' side='right' caption='[[4gs9]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
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<StructureSection load='4gs9' size='340' side='right'caption='[[4gs9]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4gs9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GS9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GS9 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gs9]] 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=4GS9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GS9 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0XB:N-(3-FLUOROPHENYL)-4-NITRO-2,1,3-BENZOXADIAZOL-5-AMINE'>0XB</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene></td></tr>
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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]] 1.72&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ghi|4ghi]], [[3h7w|3h7w]], [[3h82|3h82]], [[3f1o|3f1o]], [[3f1n|3f1n]], [[3f1p|3f1p]], [[2a24|2a24]], [[1p97|1p97]], [[1x0o|1x0o]], [[2b02|2b02]]</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=0XB:N-(3-FLUOROPHENYL)-4-NITRO-2,1,3-BENZOXADIAZOL-5-AMINE'>0XB</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BHLHE73, EPAS1, HIF2, HIF2A, MOP2, PASD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ARNT, BHLHE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4gs9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gs9 OCA], [https://pdbe.org/4gs9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gs9 RCSB], [https://www.ebi.ac.uk/pdbsum/4gs9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gs9 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gs9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gs9 OCA], [http://pdbe.org/4gs9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gs9 RCSB], [http://www.ebi.ac.uk/pdbsum/4gs9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gs9 ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN]] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:[http://omim.org/entry/611783 611783]]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.<ref>PMID:19208626</ref> <ref>PMID:18378852</ref> <ref>PMID:18184961</ref> <ref>PMID:22367913</ref>
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[https://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:[https://omim.org/entry/611783 611783]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.<ref>PMID:19208626</ref> <ref>PMID:18378852</ref> <ref>PMID:18184961</ref> <ref>PMID:22367913</ref>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN]] Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD. [[http://www.uniprot.org/uniprot/ARNT_HUMAN ARNT_HUMAN]] Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.
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[https://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN] Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2alpha-ARNT heterodimerization by binding an internal cavity of the HIF-2alpha PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2alpha-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.
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Development of Inhibitors of the PAS-B Domain of the HIF-2alpha Transcription Factor.,Rogers JL, Bayeh L, Scheuermann TH, Longgood J, Key J, Naidoo J, Melito L, Shokri C, Frantz DE, Bruick RK, Gardner KH, Macmillan JB, Tambar UK J Med Chem. 2013 Feb 18. PMID:23363003<ref>PMID:23363003</ref>
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==See Also==
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*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
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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 4gs9" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Gardner, K H]]
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[[Category: Large Structures]]
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[[Category: Scheuermann, T H]]
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[[Category: Gardner KH]]
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[[Category: Nucleus]]
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[[Category: Scheuermann TH]]
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[[Category: Pas fold]]
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[[Category: Protein-protein interaction]]
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[[Category: Transcription]]
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Current revision

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist

PDB ID 4gs9

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