6e3t: Difference between revisions
New page: '''Unreleased structure''' The entry 6e3t is ON HOLD Authors: Wu, D., Su, X., Lu, J., Li, S., Hood, B., Vasile, S., Potluri, N., Diao, X., Kim, Y., Khorasanizadeh, S., Rastinejad, F. D... |
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The | ==Crystal Structure of the Heterodimeric HIF-2 Complex with Antagonist T1001== | ||
<StructureSection load='6e3t' size='340' side='right'caption='[[6e3t]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6e3t]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E3T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E3T FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HO7:(6S)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole'>HO7</scene></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=6e3t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e3t OCA], [https://pdbe.org/6e3t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e3t RCSB], [https://www.ebi.ac.uk/pdbsum/6e3t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e3t ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ARNT_MOUSE ARNT_MOUSE] 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 (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2alpha subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2alpha chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2alpha PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2alpha agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2alpha PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2alpha-ARNT heterodimerization. | |||
Bidirectional modulation of HIF-2 activity through chemical ligands.,Wu D, Su X, Lu J, Li S, Hood BL, Vasile S, Potluri N, Diao X, Kim Y, Khorasanizadeh S, Rastinejad F Nat Chem Biol. 2019 Feb 25. pii: 10.1038/s41589-019-0234-5. doi:, 10.1038/s41589-019-0234-5. PMID:30804532<ref>PMID:30804532</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6e3t" style="background-color:#fffaf0;"></div> | ||
[[Category: Diao | |||
[[Category: | ==See Also== | ||
[[Category: | *[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]] | ||
[[Category: Kim | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mus musculus]] | ||
[[Category: Vasile | [[Category: Diao X]] | ||
[[Category: Hood B]] | |||
[[Category: Khorasanizadeh S]] | |||
[[Category: Kim Y]] | |||
[[Category: Li S]] | |||
[[Category: Lu J]] | |||
[[Category: Potluri N]] | |||
[[Category: Rastinejad F]] | |||
[[Category: Su X]] | |||
[[Category: Vasile S]] | |||
[[Category: Wu D]] | |||
Latest revision as of 09:18, 11 October 2023
Crystal Structure of the Heterodimeric HIF-2 Complex with Antagonist T1001Crystal Structure of the Heterodimeric HIF-2 Complex with Antagonist T1001
Structural highlights
FunctionARNT_MOUSE 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 (By similarity). Publication Abstract from PubMedHypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2alpha subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2alpha chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2alpha PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2alpha agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2alpha PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2alpha-ARNT heterodimerization. Bidirectional modulation of HIF-2 activity through chemical ligands.,Wu D, Su X, Lu J, Li S, Hood BL, Vasile S, Potluri N, Diao X, Kim Y, Khorasanizadeh S, Rastinejad F Nat Chem Biol. 2019 Feb 25. pii: 10.1038/s41589-019-0234-5. doi:, 10.1038/s41589-019-0234-5. PMID:30804532[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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