5tbm

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(New page: ==Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex== <StructureSection load='5tbm' size='340' side='right' caption='5tbm, resolution 1.85&Aring;' scene=''>...)
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==Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex==
==Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex==
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<StructureSection load='5tbm' size='340' side='right' caption='[[5tbm]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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<StructureSection load='5tbm' size='340' side='right'caption='[[5tbm]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5tbm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TBM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TBM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5tbm]] 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=5TBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TBM 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=79A:3-{[(1S)-2,2-DIFLUORO-1-HYDROXY-7-(METHYLSULFONYL)-2,3-DIHYDRO-1H-INDEN-4-YL]OXY}-5-FLUOROBENZONITRILE'>79A</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]] 1.85&#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=5tbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tbm OCA], [http://pdbe.org/5tbm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tbm RCSB], [http://www.ebi.ac.uk/pdbsum/5tbm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tbm 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=79A:3-{[(1S)-2,2-DIFLUORO-1-HYDROXY-7-(METHYLSULFONYL)-2,3-DIHYDRO-1H-INDEN-4-YL]OXY}-5-FLUOROBENZONITRILE'>79A</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=5tbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tbm OCA], [https://pdbe.org/5tbm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tbm RCSB], [https://www.ebi.ac.uk/pdbsum/5tbm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tbm ProSAT]</span></td></tr>
</table>
</table>
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== 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>
 
== 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/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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1alpha and HIF2alpha, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2alpha that allosterically blocks its dimerization with the HIF1alpha/2alpha transcriptional dimerization partner ARNT/HIF1beta. PT2385 inhibited the expression of HIF2alpha-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2alpha as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. (c)2016 AACR.
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A Small-Molecule Antagonist of HIF2alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.,Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, Du X, Cheng T, Czerwinski RM, Dixon DD, Goggin BS, Grina JA, Halfmann MM, Maddie MA, Olive SR, Schlachter ST, Tan H, Wang B, Wang K, Xie S, Xu R, Yang H, Josey JA Cancer Res. 2016 Sep 15;76(18):5491-500. doi: 10.1158/0008-5472.CAN-16-0473. Epub, 2016 Sep 6. PMID:27635045<ref>PMID:27635045</ref>
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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 5tbm" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
== 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 PT2385 bound to HIF2a-B*:ARNT-B* complex

PDB ID 5tbm

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