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| | ==Crystal Structure of the ARNT PAS-B homodimer== | | ==Crystal Structure of the ARNT PAS-B homodimer== |
| - | <StructureSection load='4eq1' size='340' side='right' caption='[[4eq1]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='4eq1' size='340' side='right'caption='[[4eq1]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4eq1]] is a 2 chain structure with sequence 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=4EQ1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EQ1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4eq1]] 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=4EQ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EQ1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PE5:3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL'>PE5</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1x0o|1x0o]], [[2hv1|2hv1]], [[2k7s|2k7s]], [[2b02|2b02]], [[3f1p|3f1p]], [[3f1o|3f1o]], [[3h7w|3h7w]], [[3h82|3h82]], [[3f1n|3f1n]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PE5:3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL'>PE5</scene></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 Homo sapiens])</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=4eq1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eq1 OCA], [https://pdbe.org/4eq1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eq1 RCSB], [https://www.ebi.ac.uk/pdbsum/4eq1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eq1 ProSAT]</span></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=4eq1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eq1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eq1 RCSB], [http://www.ebi.ac.uk/pdbsum/4eq1 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == 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. | + | [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;">
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| - | == Publication Abstract from PubMed ==
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| - | For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used in vitro NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1alpha. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors.
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| - | Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules.,Guo Y, Partch CL, Key J, Card PB, Pashkov V, Patel A, Bruick RK, Wurdak H, Gardner KH ACS Chem Biol. 2013 Mar 15;8(3):626-35. doi: 10.1021/cb300604u. Epub 2012 Dec 26. PMID:23240775<ref>PMID:23240775</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | ==See Also== |
| - | </div>
| + | *[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]] |
| - | == References == | + | |
| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Gardner, K H]] | + | [[Category: Large Structures]] |
| - | [[Category: Key, J M]] | + | [[Category: Gardner KH]] |
| - | [[Category: Ahr]] | + | [[Category: Key JM]] |
| - | [[Category: Dna-binding]]
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| - | [[Category: Hif1]]
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| - | [[Category: Hif2]]
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| - | [[Category: Homodimer]]
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| - | [[Category: Per-arnt-sim]]
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| - | [[Category: Transcription]]
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| - | [[Category: Transcription factor]]
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| - | [[Category: Transcription regulation]]
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