5kiz

From Proteopedia

(Difference between revisions)

Current revision

Solution Structure of a repacked version of HIF-2 alpha PAS-B

Structural highlights

5kiz is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
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.

Publication Abstract from PubMed

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors central to hypoxia response and cancer development. Within the HIF-2 complex, one domain (HIF-2alpha PAS-B) contains a large (290 A(3)) buried cavity filled with water molecules within its hydrophobic core. Such cavities are uncommon except in the case of ligand-binding proteins, leading to the hypothesis that HIF-2alpha can be regulated by small molecules. The development of artificial HIF-2alpha inhibitors validates this hypothesis but raises questions about the impact of this cavity on HIF-2alpha PAS-B structure and function. To answer these points, we used computational methods to construct a repacked protein containing a smaller cavity within the native fold. Experimental validation of a five-mutation variant confirms achieving these objectives and stabilizing the folded structure. Complementary functional data establish that ligands cannot bind this variant although heterodimerization remains unchanged. Altogether, our strategy innovatively addresses the roles of solvated cavities in maintaining protein stability and function.

Computational Repacking of HIF-2alpha Cavity Replaces Water-Based Stabilized Core.,Correa F, Key J, Kuhlman B, Gardner KH Structure. 2016 Nov 1;24(11):1918-1927. doi: 10.1016/j.str.2016.08.014. Epub 2016, Sep 22. PMID:27667693^[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
↑ Correa F, Key J, Kuhlman B, Gardner KH. Computational Repacking of HIF-2alpha Cavity Replaces Water-Based Stabilized Core. Structure. 2016 Nov 1;24(11):1918-1927. doi: 10.1016/j.str.2016.08.014. Epub 2016, Sep 22. PMID:27667693 doi:http://dx.doi.org/10.1016/j.str.2016.08.014

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Solution Structure of a repacked version of HIF-2 alpha PAS-B==
-<StructureSection load='5kiz' size='340' side='right'caption='[[5kiz]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='5kiz' size='340' side='right'caption='[[5kiz]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5kiz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KIZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5kiz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KIZ FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPAS1, BHLHE73, HIF2A, MOP2, PASD2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kiz OCA], [https://pdbe.org/5kiz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kiz RCSB], [https://www.ebi.ac.uk/pdbsum/5kiz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kiz ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kiz OCA], [https://pdbe.org/5kiz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kiz RCSB], [https://www.ebi.ac.uk/pdbsum/5kiz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kiz ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[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>
+[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 ==
-[[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.
+[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.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 5kiz" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[3D structures of hypoxia-inducible factor|3D structures of hypoxia-inducible factor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Correa, F]]
+[[Category: Correa F]]
-[[Category: Gardner, K H]]
+[[Category: Gardner KH]]
-[[Category: Key, J]]
+[[Category: Key J]]
-[[Category: Kuhlman, B]]
+[[Category: Kuhlman B]]
-[[Category: Cavity]]
-[[Category: Repacking]]
-[[Category: Rosetta]]
-[[Category: Transcription]]

5kiz

From Proteopedia

Current revision

Solution Structure of a repacked version of HIF-2 alpha PAS-B

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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