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3f1n

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Revision as of 09:24, 25 October 2017

Crystal structure of a high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains, with internally bound ethylene glycol.

Structural highlights

3f1n 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:	1x0o, 1p97, 2b02, 2a24, 3f1o, 3f1p
Gene:	EPAS1, HIF2A, Hypoxia-Inducible Factor 2 alpha, MOP2 (HUMAN), ARNT, Aryl Hydrocarbon Receptor Nuclear Translocator (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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The hypoxia-inducible factor (HIF) basic helix-loop-helix Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (bHLH-PAS) transcription factors are master regulators of the conserved molecular mechanism by which metazoans sense and respond to reductions in local oxygen concentrations. In humans, HIF is critically important for the sustained growth and metastasis of solid tumors. Here, we describe crystal structures of the heterodimer formed by the C-terminal PAS domains from the HIF2alpha and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2alpha PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2alpha PAS-B modulates the affinity of the HIF2alpha:ARNT PAS-B heterodimer in vitro. Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings.

Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor.,Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):450-5. Epub 2009 Jan 7. PMID:19129502^[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, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):450-5. Epub 2009 Jan 7. PMID:19129502

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3f1n"

@@ Line 1: / Line 1: @@
 ==Crystal structure of a high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains, with internally bound ethylene glycol.==
 <StructureSection load='3f1n' size='340' side='right' caption='[[3f1n]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1x0o|1x0o]], [[1p97|1p97]], [[2b02|2b02]], [[2a24|2a24]], [[3f1o|3f1o]], [[3f1p|3f1p]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPAS1, HIF2A, Hypoxia-Inducible Factor 2 alpha, MOP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ARNT, Aryl Hydrocarbon Receptor Nuclear Translocator ([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=3f1n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f1n OCA], [http://pdbe.org/3f1n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3f1n RCSB], [http://www.ebi.ac.uk/pdbsum/3f1n 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=3f1n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f1n OCA], [http://pdbe.org/3f1n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3f1n RCSB], [http://www.ebi.ac.uk/pdbsum/3f1n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3f1n ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 31: / Line 32: @@
 </div>
 <div class="pdbe-citations 3f1n" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Factor inhibiting HIF|Factor inhibiting HIF]]
 == References ==
 <references/>
@@ Line 46: / Line 44: @@
 [[Category: Tomchick, D R]]
 [[Category: Activator]]
+[[Category: Alternative splicing]]
 [[Category: Angiogenesis]]
 [[Category: Congenital erythrocytosis]]
@@ Line 58: / Line 57: @@
 [[Category: Pas domain]]
 [[Category: Phosphoprotein]]
+[[Category: Polymorphism]]
 [[Category: Transcription]]
 [[Category: Transcription regulation]]
+[[Category: Ubl conjugation]]

3f1n

From Proteopedia

Revision as of 09:24, 25 October 2017

Crystal structure of a high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains, with internally bound ethylene glycol.

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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