5ufp

From Proteopedia

(Difference between revisions)

Revision as of 10:24, 22 November 2017

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

Structural highlights

5ufp is a 2 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 5t0t. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	EPAS1, BHLHE73, HIF2A, MOP2, PASD2 (HUMAN), ARNT, BHLHE2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EPAS1_HUMAN] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM: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.^[1] ^[2] ^[3] ^[4]

Function

[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. [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.

Publication Abstract from PubMed

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.

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TR, Lee FS. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009 Apr 3;284(14):9050-8. doi: 10.1074/jbc.M808737200. Epub 2009, Feb 10. PMID:19208626 doi:10.1074/jbc.M808737200
↑ Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood. 2008 Jun 1;111(11):5400-2. doi: 10.1182/blood-2008-02-137703. Epub 2008, Mar 31. PMID:18378852 doi:10.1182/blood-2008-02-137703
↑ Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med. 2008 Jan 10;358(2):162-8. doi: 10.1056/NEJMoa073123. PMID:18184961 doi:10.1056/NEJMoa073123
↑ Percy MJ, Chung YJ, Harrison C, Mercieca J, Hoffbrand AV, Dinardo CL, Santos PC, Fonseca GH, Gualandro SF, Pereira AC, Lappin TR, McMullin MF, Lee FS. Two new mutations in the HIF2A gene associated with erythrocytosis. Am J Hematol. 2012 Apr;87(4):439-42. doi: 10.1002/ajh.23123. Epub 2012 Feb 24. PMID:22367913 doi:10.1002/ajh.23123
↑ 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. On-Target Efficacy of a HIF2alpha Antagonist in Preclinical Kidney Cancer Models. Nature. 2016 Sep 5. doi: 10.1038/nature19795. PMID:27595393 doi:http://dx.doi.org/10.1038/nature19795

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ufp"

Categories: Human | Du, X | Hif2 inhibitor hif2 ligand pas-b hypoxia inducible factor 2 epas1 | Transcription

@@ Line 3: / Line 3: @@
 <StructureSection load='5ufp' size='340' side='right' caption='[[5ufp]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<table><tr><td colspan='2'>[[5ufp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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>
 </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>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPAS1, BHLHE73, HIF2A, MOP2, PASD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ARNT, BHLHE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=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>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Du, X]]
 [[Category: Hif2 inhibitor hif2 ligand pas-b hypoxia inducible factor 2 epas1]]
 [[Category: Transcription]]

5ufp

From Proteopedia

Revision as of 10:24, 22 November 2017

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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Views

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5ufp

From Proteopedia

Revision as of 10:24, 22 November 2017

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox

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