View source for 5lbb


==HIF prolyl hydroxylase 2 (PHD2/EGLN1) R396T variant in complex with Mn(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/UN9)==
<StructureSection load='5lbb' size='340' side='right' caption='[[5lbb]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lbb]] is a 1 chain structure. 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LBB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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='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://oca.weizmann.ac.il/oca-docs/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>
== 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>  
== 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>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:27561929</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lbb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hypoxia-inducible factor-proline dioxygenase]]
[[Category: Chowdhury, R]]
[[Category: Schofield, C J]]
[[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]]