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| | <StructureSection load='4xt2' size='340' side='right'caption='[[4xt2]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='4xt2' size='340' side='right'caption='[[4xt2]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xt2]] is a 4 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=4XT2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XT2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xt2]] is a 4 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=4XT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XT2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=43L:(5S,7R)-5,7-BIS(3-BROMOPHENYL)-4,5,6,7-TETRAHYDROTETRAZOLO[1,5-A]PYRIMIDINE'>43L</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=43L:(5S,7R)-5,7-BIS(3-BROMOPHENYL)-4,5,6,7-TETRAHYDROTETRAZOLO[1,5-A]PYRIMIDINE'>43L</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3f1p|3f1p]], [[3f1o|3f1o]], [[3hw7|3hw7]], [[3h82|3h82]], [[4ghi|4ghi]], [[4gs9|4gs9]], [[4lpz|4lpz]]</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=4xt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xt2 OCA], [https://pdbe.org/4xt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xt2 RCSB], [https://www.ebi.ac.uk/pdbsum/4xt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xt2 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARNT, BHLHE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EPAS1, BHLHE73, HIF2A, MOP2, PASD2 ([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=4xt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xt2 OCA], [http://pdbe.org/4xt2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xt2 RCSB], [http://www.ebi.ac.uk/pdbsum/4xt2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xt2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == 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> | |
| | == Function == | | == Function == |
| - | [[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. [[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. | + | [https://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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gardner, K H]] | + | [[Category: Gardner KH]] |
| - | [[Category: Scheuermann, T H]] | + | [[Category: Scheuermann TH]] |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Hypoxia inducible factor]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2alpha subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.
Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.,Scheuermann TH, Stroud D, Sleet CE, Bayeh L, Shokri C, Wang H, Caldwell CG, Longgood J, MacMillan JB, Bruick RK, Gardner KH, Tambar UK J Med Chem. 2015 Aug 13;58(15):5930-41. doi: 10.1021/acs.jmedchem.5b00529. Epub, 2015 Jul 30. PMID:26226049[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Scheuermann TH, Stroud D, Sleet CE, Bayeh L, Shokri C, Wang H, Caldwell CG, Longgood J, MacMillan JB, Bruick RK, Gardner KH, Tambar UK. Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2. J Med Chem. 2015 Aug 13;58(15):5930-41. doi: 10.1021/acs.jmedchem.5b00529. Epub, 2015 Jul 30. PMID:26226049 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00529
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