4ghi

From Proteopedia

(Difference between revisions)

Revision as of 09:11, 11 August 2016

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist

Structural highlights

4ghi is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3h7w, 3h82, 3f1n, 3f1o, 3f1p, 2hv1
Gene:	BHLHE73, EPAS1, 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

Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2alpha subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2alpha and HIF-1alpha, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas.

Allosteric inhibition of hypoxia inducible factor-2 with small molecules.,Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK Nat Chem Biol. 2013 Apr;9(4):271-6. doi: 10.1038/nchembio.1185. Epub 2013 Feb 24. PMID:23434853^[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
↑ Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol. 2013 Apr;9(4):271-6. doi: 10.1038/nchembio.1185. Epub 2013 Feb 24. PMID:23434853 doi:http://dx.doi.org/10.1038/nchembio.1185

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/4ghi"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist==
 <StructureSection load='4ghi' size='340' side='right' caption='[[4ghi]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4ghi]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GHI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4ghi]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GHI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0X3:N-(3-CHLORO-5-FLUOROPHENYL)-4-NITRO-2,1,3-BENZOXADIAZOL-5-AMINE'>0X3</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h7w|3h7w]], [[3h82|3h82]], [[3f1n|3f1n]], [[3f1o|3f1o]], [[3f1p|3f1p]], [[2hv1|2hv1]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BHLHE73, EPAS1, HIF2A, MOP2, PASD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), ARNT, BHLHE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BHLHE73, EPAS1, 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=4ghi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ghi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ghi RCSB], [http://www.ebi.ac.uk/pdbsum/4ghi PDBsum]</span></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=4ghi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ghi OCA], [http://pdbe.org/4ghi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ghi RCSB], [http://www.ebi.ac.uk/pdbsum/4ghi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ghi ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4ghi" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Bruick, R K]]
 [[Category: Gardner, K H]]

4ghi

From Proteopedia

Revision as of 09:11, 11 August 2016

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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