5v18

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'''Unreleased structure'''
 
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The entry 5v18 is ON HOLD until Paper Publication
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==Structure of PHD2 in complex with 1,2,4-Triazolo-[1,5-a]pyridine==
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<StructureSection load='5v18' size='340' side='right' caption='[[5v18]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5v18]] 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=5V18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V18 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=8UY:4-([1,2,4]triazolo[1,5-a]pyridin-5-yl)benzonitrile'>8UY</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v1b|5v1b]]</td></tr>
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<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>
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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='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=5v18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v18 OCA], [http://pdbe.org/5v18 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v18 RCSB], [http://www.ebi.ac.uk/pdbsum/5v18 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v18 ProSAT]</span></td></tr>
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</table>
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== 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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== 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
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Authors: Skene, R.J.
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1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.,Ahmed S, Ayscough A, Barker GR, Canning HE, Davenport R, Downham R, Harrison D, Jenkins K, Kinsella N, Livermore DG, Wright S, Ivetac AD, Skene R, Wilkens SJ, Webster NA, Hendrick AG J Med Chem. 2017 Jul 13;60(13):5663-5672. doi: 10.1021/acs.jmedchem.7b00352. Epub, 2017 Jun 24. PMID:28594552<ref>PMID:28594552</ref>
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Description: Structure of PHD2 in complex with 1,2,4-Triazolo-[1,5-a]pyridine
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Skene, R.J]]
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<div class="pdbe-citations 5v18" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Hypoxia-inducible factor-proline dioxygenase]]
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[[Category: Skene, R J]]
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[[Category: Hif prolylhydroxylase domain-2]]
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[[Category: Inhibitor]]
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[[Category: Momodentate binding]]
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[[Category: Oxidoreductase-inhibitor complex]]

Revision as of 06:10, 16 November 2017

Structure of PHD2 in complex with 1,2,4-Triazolo-[1,5-a]pyridine

5v18, resolution 2.15Å

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