5a3u: Difference between revisions
New page: '''Unreleased structure''' The entry 5a3u is ON HOLD Authors: CHOWDHURY, R., Gomez-Perez, V., SCHOFIELD, C.J. Description: HIF prolyl hydroxylase 2 (PHD2 EGLN1) in complex with 6-(5-ox... |
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==HIF prolyl hydroxylase 2 (PHD2/EGLN1) in complex with 6-(5-oxo-4-(1H- 1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinic acid== | |||
<StructureSection load='5a3u' size='340' side='right'caption='[[5a3u]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5a3u]] is a 3 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=5A3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A3U 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]] 3.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=R8J:6-(5-OXO-4-(1H-1,2,3-TRIAZOL-1-YL)-2,5-DIHYDRO-1H-PYRAZOL-1-YL)NICOTINIC+ACID'>R8J</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=5a3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a3u OCA], [https://pdbe.org/5a3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a3u RCSB], [https://www.ebi.ac.uk/pdbsum/5a3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a3u 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFalpha in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke. | |||
Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.,Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IK, Chowdhury R, Gomez-Perez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian YM, Bishop T, Claridge TD, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ PLoS One. 2015 Jul 6;10(7):e0132004. doi: 10.1371/journal.pone.0132004., eCollection 2015. PMID:26147748<ref>PMID:26147748</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5a3u" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Gomez-Perez | ==See Also== | ||
*[[Polyl hydroxylase domain 3D structures|Polyl hydroxylase domain 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chowdhury R]] | |||
[[Category: Gomez-Perez V]] | |||
[[Category: Schofield CJ]] | |||
Latest revision as of 14:03, 10 January 2024
HIF prolyl hydroxylase 2 (PHD2/EGLN1) in complex with 6-(5-oxo-4-(1H- 1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinic acidHIF prolyl hydroxylase 2 (PHD2/EGLN1) in complex with 6-(5-oxo-4-(1H- 1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinic acid
Structural highlights
DiseaseEGLN1_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] FunctionEGLN1_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 PubMedAs part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFalpha in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke. Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.,Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IK, Chowdhury R, Gomez-Perez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian YM, Bishop T, Claridge TD, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ PLoS One. 2015 Jul 6;10(7):e0132004. doi: 10.1371/journal.pone.0132004., eCollection 2015. PMID:26147748[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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