View source for 4xt2


==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a tetrazole-containing antagonist==
<StructureSection load='4xt2' size='340' side='right'caption='[[4xt2]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.698&#8491;</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='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>
</table>
== Function ==
[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;">
== 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<ref>PMID:26226049</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4xt2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gardner KH]]
[[Category: Scheuermann TH]]