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| | ==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist== | | ==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist== |
| - | <StructureSection load='4ghi' size='340' side='right' caption='[[4ghi]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='4ghi' size='340' side='right'caption='[[4ghi]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ghi]] 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=4GHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GHI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ghi]] 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=4GHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GHI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0X3:N-(3-CHLORO-5-FLUOROPHENYL)-4-NITRO-2,1,3-BENZOXADIAZOL-5-AMINE'>0X3</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0X3:N-(3-CHLORO-5-FLUOROPHENYL)-4-NITRO-2,1,3-BENZOXADIAZOL-5-AMINE'>0X3</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h7w|3h7w]], [[3h82|3h82]], [[3f1n|3f1n]], [[3f1o|3f1o]], [[3f1p|3f1p]], [[2hv1|2hv1]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ghi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ghi OCA], [https://pdbe.org/4ghi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ghi RCSB], [https://www.ebi.ac.uk/pdbsum/4ghi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ghi ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BHLHE73, EPAS1, 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>
| + | |
| - | <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=4ghi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ghi OCA], [http://pdbe.org/4ghi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ghi RCSB], [http://www.ebi.ac.uk/pdbsum/4ghi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ghi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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 == |
| - | [[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. | + | [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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ghi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ghi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Bruick, R K]] | + | [[Category: Large Structures]] |
| - | [[Category: Gardner, K H]] | + | [[Category: Bruick RK]] |
| - | [[Category: Key, J]] | + | [[Category: Gardner KH]] |
| - | [[Category: Scheuermann, T H]] | + | [[Category: Key J]] |
| - | [[Category: Tambar, U K]] | + | [[Category: Scheuermann TH]] |
| - | [[Category: Pas fold]] | + | [[Category: Tambar UK]] |
| - | [[Category: Protein : protein interaction]]
| + | |
| - | [[Category: Transcription]]
| + | |
| Structural highlights
Disease
EPAS1_HUMAN Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM: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.[1] [2] [3] [4]
Function
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.
Publication Abstract from PubMed
Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2alpha subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2alpha and HIF-1alpha, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas.
Allosteric inhibition of hypoxia inducible factor-2 with small molecules.,Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK Nat Chem Biol. 2013 Apr;9(4):271-6. doi: 10.1038/nchembio.1185. Epub 2013 Feb 24. PMID:23434853[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TR, Lee FS. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009 Apr 3;284(14):9050-8. doi: 10.1074/jbc.M808737200. Epub 2009, Feb 10. PMID:19208626 doi:10.1074/jbc.M808737200
- ↑ Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood. 2008 Jun 1;111(11):5400-2. doi: 10.1182/blood-2008-02-137703. Epub 2008, Mar 31. PMID:18378852 doi:10.1182/blood-2008-02-137703
- ↑ Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med. 2008 Jan 10;358(2):162-8. doi: 10.1056/NEJMoa073123. PMID:18184961 doi:10.1056/NEJMoa073123
- ↑ Percy MJ, Chung YJ, Harrison C, Mercieca J, Hoffbrand AV, Dinardo CL, Santos PC, Fonseca GH, Gualandro SF, Pereira AC, Lappin TR, McMullin MF, Lee FS. Two new mutations in the HIF2A gene associated with erythrocytosis. Am J Hematol. 2012 Apr;87(4):439-42. doi: 10.1002/ajh.23123. Epub 2012 Feb 24. PMID:22367913 doi:10.1002/ajh.23123
- ↑ Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol. 2013 Apr;9(4):271-6. doi: 10.1038/nchembio.1185. Epub 2013 Feb 24. PMID:23434853 doi:http://dx.doi.org/10.1038/nchembio.1185
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