5ox6

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==HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Vadadustat==
==HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Vadadustat==
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<StructureSection load='5ox6' size='340' side='right' caption='[[5ox6]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
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<StructureSection load='5ox6' size='340' side='right'caption='[[5ox6]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ox6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OX6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OX6 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ox6]] 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=5OX6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OX6 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A1Z:Vadadustat'>A1Z</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hypoxia-inducible_factor-proline_dioxygenase Hypoxia-inducible factor-proline dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.29 1.14.11.29] </span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1Z:Vadadustat'>A1Z</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<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=5ox6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ox6 OCA], [http://pdbe.org/5ox6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ox6 RCSB], [http://www.ebi.ac.uk/pdbsum/5ox6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ox6 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ox6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ox6 OCA], [https://pdbe.org/5ox6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ox6 RCSB], [https://www.ebi.ac.uk/pdbsum/5ox6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ox6 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/EGLN1_HUMAN EGLN1_HUMAN]] Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:[http://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>
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[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 ==
== Function ==
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[[http://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>
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[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>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-alpha isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic and cellular profiling studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals.
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Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-alpha oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations.
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Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases.,Chowdhury R, Candela-Lena JI, Chan MC, Greenald DJ, Yeoh KK, Tian YM, McDonough MA, Tumber A, Rose NR, Conejo-Garcia A, Demetriades M, Mathavan S, Kawamura A, Lee MK, van Eeden F, Pugh CW, Ratcliffe PJ, Schofield CJ ACS Chem Biol. 2013 May 17. PMID:23683440<ref>PMID:23683440</ref>
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Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.,Yeh TL, Leissing TM, Abboud MI, Thinnes CC, Atasoylu O, Holt-Martyn JP, Zhang D, Tumber A, Lippl K, Lohans CT, Leung IKH, Morcrette H, Clifton IJ, Claridge TDW, Kawamura A, Flashman E, Lu X, Ratcliffe PJ, Chowdhury R, Pugh CW, Schofield CJ Chem Sci. 2017 Nov 1;8(11):7651-7668. doi: 10.1039/c7sc02103h. Epub 2017 Sep 11. PMID:29435217<ref>PMID:29435217</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 5ox6" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5ox6" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Polyl hydroxylase domain 3D structures|Polyl hydroxylase domain 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Hypoxia-inducible factor-proline dioxygenase]]
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[[Category: Homo sapiens]]
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[[Category: Chowdhury, R]]
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[[Category: Large Structures]]
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[[Category: Schofield, C J]]
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[[Category: Chowdhury R]]
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[[Category: Zhang, D]]
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[[Category: Schofield CJ]]
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[[Category: 2-oxoglutarate]]
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[[Category: Zhang D]]
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[[Category: Beta-hydroxylation]]
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[[Category: Breast cancer]]
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[[Category: Cell structure]]
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[[Category: Cytoplasm]]
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[[Category: Development]]
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[[Category: Dna-binding]]
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[[Category: Dsbh]]
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[[Category: Egln1]]
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[[Category: Facial triad]]
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[[Category: Familial erythrocytosis]]
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[[Category: Helix-loop-helix-beta]]
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[[Category: Hif]]
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[[Category: Hif prolyl hydroxylase domain 2]]
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[[Category: Hypoxia]]
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[[Category: Hypoxia-inducible factor]]
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[[Category: Iron]]
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[[Category: Metal-binding]]
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[[Category: Non-heme dioxygenase]]
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[[Category: Oxidoreductase]]
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[[Category: Oxygenase]]
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[[Category: Phd2]]
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[[Category: Polymorphism]]
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[[Category: Signaling]]
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[[Category: Transcription]]
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[[Category: Transcription activator/inhibitor]]
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[[Category: Transcription complex]]
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[[Category: Transcription/epigenetic regulation]]
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[[Category: Ubl conjugation]]
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[[Category: Vitamin c]]
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[[Category: Zinc-finger]]
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Current revision

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with Vadadustat

PDB ID 5ox6

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