5ufp

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==Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex==
==Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex==
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<StructureSection load='5ufp' size='340' side='right' caption='[[5ufp]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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<StructureSection load='5ufp' size='340' side='right'caption='[[5ufp]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ufp]] is a 2 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5t0t 5t0t]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UFP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UFP FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ufp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5t0t 5t0t]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UFP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UFP FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=86D:3-({(1S)-7-[(DIFLUOROMETHYL)SULFONYL]-2,2-DIFLUORO-1-HYDROXY-2,3-DIHYDRO-1H-INDEN-4-YL}OXY)-5-FLUOROBENZONITRILE'>86D</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<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=5ufp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ufp OCA], [http://pdbe.org/5ufp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ufp RCSB], [http://www.ebi.ac.uk/pdbsum/5ufp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ufp ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86D:3-({(1S)-7-[(DIFLUOROMETHYL)SULFONYL]-2,2-DIFLUORO-1-HYDROXY-2,3-DIHYDRO-1H-INDEN-4-YL}OXY)-5-FLUOROBENZONITRILE'>86D</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ufp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ufp OCA], [https://pdbe.org/5ufp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ufp RCSB], [https://www.ebi.ac.uk/pdbsum/5ufp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ufp ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
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[[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.
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[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.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2alpha transcription factor 1. Here we show that a small molecule (PT2399) that directly inhibits HIF2alpha causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion. pVHL-defective ccRCC cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers.
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On-Target Efficacy of a HIF2alpha Antagonist in Preclinical Kidney Cancer Models.,Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick R, Josey JA, Wallace EM, Kaelin WG Jr Nature. 2016 Sep 5. doi: 10.1038/nature19795. PMID:27595393<ref>PMID:27595393</ref>
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==See Also==
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*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5ufp" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Du, X]]
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[[Category: Homo sapiens]]
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[[Category: Hif2 inhibitor hif2 ligand pas-b hypoxia inducible factor 2 epas1]]
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[[Category: Large Structures]]
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[[Category: Transcription]]
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[[Category: Du X]]

Current revision

Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex

PDB ID 5ufp

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