2g19: Difference between revisions

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-[[Image:2g19.gif|left|200px]]<br />
-<applet load="2g19" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2g19, resolution 1.70&Aring;" />
-'''Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)'''<br />
-==Overview==
+==Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)==
-Cellular and physiological responses to changes in dioxygen levels in, metazoans are mediated via the posttranslational oxidation of, hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved, prolyl residues in the HIF-alpha subunit, catalyzed by HIF, prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The, requirement of the PHDs for dioxygen links changes in dioxygen levels with, the transcriptional regulation of the gene array that enables the cellular, response to chronic hypoxia; the PHDs thus act as an oxygen-sensing, component of the HIF system, and their inhibition mimics the hypoxic, response. We describe crystal structures of the catalytic domain of human, PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in, normal cells, in complex with Fe(II) and an inhibitor to 1.7 A resolution., PHD2 crystallizes as a homotrimer and contains a double-stranded, beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant, dioxygenase family, the residues of which are well conserved in the three, human PHD enzymes (PHD 1-3). The structure provides insights into the, hypoxic response, helps to rationalize a clinically observed mutation, leading to familial erythrocytosis, and will aid in the design of PHD, selective inhibitors for the treatment of anemia and ischemic disease.
+<StructureSection load='2g19' size='340' side='right'caption='[[2g19]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2g19]] is a 1 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=2G19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G19 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4HG:N-[(4-HYDROXY-8-IODOISOQUINOLIN-3-YL)CARBONYL]GLYCINE'>4HG</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene></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=2g19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g19 OCA], [https://pdbe.org/2g19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g19 RCSB], [https://www.ebi.ac.uk/pdbsum/2g19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g19 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/EGLN1_HUMAN EGLN1_HUMAN] Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:[https://omim.org/entry/609820 609820]. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.<ref>PMID:16407130</ref> <ref>PMID:17579185</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/EGLN1_HUMAN EGLN1_HUMAN] Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.<ref>PMID:11595184</ref> <ref>PMID:12351678</ref> <ref>PMID:15897452</ref> <ref>PMID:19339211</ref> <ref>PMID:21792862</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g1/2g19_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2g19 ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known disease associated with this structure: Erythrocytosis, familial, 3 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606425 606425]]
+*[[Polyl hydroxylase domain 3D structures|Polyl hydroxylase domain 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-G19 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FE2 and 4HG as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2G19 OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)., McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Lienard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J, McNeill LA, Kurzeja RJ, Hewitson KS, Yang E, Jordan S, Syed RS, Schofield CJ, Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9. Epub 2006 Jun 16. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16782814 16782814]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Li, V.]]
+[[Category: Li V]]
-[[Category: Syed, R.S.]]
+[[Category: Syed RS]]
-[[Category: 4HG]]
-[[Category: FE2]]
-[[Category: 2-oxoglutarate]]
-[[Category: dsbh]]
-[[Category: egln]]
-[[Category: hif]]
-[[Category: hph]]
-[[Category: hydroxylase]]
-[[Category: hypoxia]]
-[[Category: oxygenase]]
-[[Category: phd2]]
-[[Category: prolyl hydroxylase]]
-[[Category: transcription]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:12:50 2007''