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| | <StructureSection load='5lbb' size='340' side='right'caption='[[5lbb]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='5lbb' size='340' side='right'caption='[[5lbb]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lbb]] is a 1 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=5LBB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LBB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lbb]] 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=5LBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LBB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UN9:N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE'>UN9</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hqr|3hqr]], [[4bqx|4bqx]], [[5l9b|5l9b]], [[5l9v|5l9v]], [[5l9r|5l9r]], [[5la9|5la9]], [[5las|5las]], [[5lat|5lat]], [[5lb6|5lb6]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UN9:N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE'>UN9</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EGLN1, C1orf12, PNAS-118, PNAS-137 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=5lbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lbb OCA], [https://pdbe.org/5lbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lbb RCSB], [https://www.ebi.ac.uk/pdbsum/5lbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lbb ProSAT]</span></td></tr> |
| - | <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>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5lbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lbb OCA], [http://pdbe.org/5lbb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lbb RCSB], [http://www.ebi.ac.uk/pdbsum/5lbb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lbb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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 == |
| - | [[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> | + | [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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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Hydroxylases 3D structures|Hydroxylases 3D structures]] | + | *[[Polyl hydroxylase domain 3D structures|Polyl hydroxylase domain 3D structures]] |
| - | *[[Prolyl hydroxylase domain|Prolyl hydroxylase domain]]
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hypoxia-inducible factor-proline dioxygenase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chowdhury, R]] | + | [[Category: Chowdhury R]] |
| - | [[Category: Schofield, C J]] | + | [[Category: Schofield CJ]] |
| - | [[Category: 2-oxoglutarate]]
| + | |
| - | [[Category: Beta-hydroxylation]]
| + | |
| - | [[Category: Breast cancer]]
| + | |
| - | [[Category: Cell structure]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Development]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Dsbh]]
| + | |
| - | [[Category: Egln1]]
| + | |
| - | [[Category: Facial triad]]
| + | |
| - | [[Category: Familial erythrocytosis]]
| + | |
| - | [[Category: Helix-loop-helix-beta]]
| + | |
| - | [[Category: Hif]]
| + | |
| - | [[Category: Hif prolyl hydroxylase domain 2]]
| + | |
| - | [[Category: Hypoxia]]
| + | |
| - | [[Category: Hypoxia-inducible factor]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Non-heme dioxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxygenase]]
| + | |
| - | [[Category: Phd2]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Signaling]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription activator/inhibitor]]
| + | |
| - | [[Category: Transcription complex]]
| + | |
| - | [[Category: Transcription/epigenetic regulation]]
| + | |
| - | [[Category: Ubl conjugation]]
| + | |
| - | [[Category: Vitamin c]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Disease
EGLN1_HUMAN Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM: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.[1] [2]
Function
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.[3] [4] [5] [6] [7]
Publication Abstract from PubMed
The response to hypoxia in animals involves the expression of multiple genes regulated by the alphabeta-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFalpha isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFalpha to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFalpha. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.
Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.,Chowdhury R, Leung IK, Tian YM, Abboud MI, Ge W, Domene C, Cantrelle FX, Landrieu I, Hardy AP, Pugh CW, Ratcliffe PJ, Claridge TD, Schofield CJ Nat Commun. 2016 Aug 26;7:12673. doi: 10.1038/ncomms12673. PMID:27561929[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. Epub 2006 Jan 9. PMID:16407130 doi:0508423103
- ↑ Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007 Sep 15;110(6):2193-6. Epub 2007 Jun 19. PMID:17579185 doi:10.1182/blood-2007-04-084434
- ↑ Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. PMID:11595184
- ↑ Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13459-64. Epub 2002 Sep 26. PMID:12351678 doi:10.1073/pnas.192342099
- ↑ Ozer A, Wu LC, Bruick RK. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005 May 24;102(21):7481-6. Epub 2005 May 16. PMID:15897452 doi:0502716102
- ↑ Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K. Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009 May;1793(5):792-7. doi: 10.1016/j.bbamcr.2009.01.014. , Epub 2009 Feb 5. PMID:19339211 doi:10.1016/j.bbamcr.2009.01.014
- ↑ Su Y, Loos M, Giese N, Metzen E, Buchler MW, Friess H, Kornberg A, Buchler P. Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer. 2012 Feb 15;118(4):960-72. doi: 10.1002/cncr.26344. Epub 2011 Jul 26. PMID:21792862 doi:10.1002/cncr.26344
- ↑ Chowdhury R, Leung IK, Tian YM, Abboud MI, Ge W, Domene C, Cantrelle FX, Landrieu I, Hardy AP, Pugh CW, Ratcliffe PJ, Claridge TD, Schofield CJ. Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases. Nat Commun. 2016 Aug 26;7:12673. doi: 10.1038/ncomms12673. PMID:27561929 doi:http://dx.doi.org/10.1038/ncomms12673
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