9wy2: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The~~ entry ~~9wy2~~ is ~~ON HOLD until Paper~~ Publication

==Crystal Structure of HIF-PHD2 in complex with compound 3-2==

== Structural highlights ==

<table><tr><td colspan='2'>[[9wy2]] 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=9WY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WY2 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]] 1.9Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MCD:4-oxidanyl-~{N}-(2-phenylpropan-2-yl)-2-pyrazol-1-yl-pyrimidine-5-carboxamide'>A1MCD</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</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=9wy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wy2 OCA], [https://pdbe.org/9wy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wy2 RCSB], [https://www.ebi.ac.uk/pdbsum/9wy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wy2 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>

== Publication Abstract from PubMed ==

The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.

~~Authors~~:

Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor.,Fukuda T, Nishi T, Ishiyama T, Kitazawa R, Ishii K, Takahashi S, Kawabata Y, Yamaguchi K, Baba D, Ito S, Tanaka N Bioorg Med Chem Lett. 2026 Feb 1;131:130476. doi: 10.1016/j.bmcl.2025.130476. , Epub 2025 Nov 19. PMID:41265580<ref>PMID:41265580</ref>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Baba D]]

[[Category: Fukuda T]]

[[Category: Ito S]]

[[Category: Tanaka N]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9wy2 is ON HOLD  until Paper Publication
+==Crystal Structure of HIF-PHD2 in complex with compound 3-2==
+<StructureSection load='9wy2' size='340' side='right'caption='[[9wy2]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9wy2]] 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=9WY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WY2 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]] 1.9&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MCD:4-oxidanyl-~{N}-(2-phenylpropan-2-yl)-2-pyrazol-1-yl-pyrimidine-5-carboxamide'>A1MCD</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</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=9wy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wy2 OCA], [https://pdbe.org/9wy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wy2 RCSB], [https://www.ebi.ac.uk/pdbsum/9wy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wy2 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 ==
+The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.
-Authors:
+Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor.,Fukuda T, Nishi T, Ishiyama T, Kitazawa R, Ishii K, Takahashi S, Kawabata Y, Yamaguchi K, Baba D, Ito S, Tanaka N Bioorg Med Chem Lett. 2026 Feb 1;131:130476. doi: 10.1016/j.bmcl.2025.130476. , Epub 2025 Nov 19. PMID:41265580<ref>PMID:41265580</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9wy2" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Baba D]]
+[[Category: Fukuda T]]
+[[Category: Ito S]]
+[[Category: Tanaka N]]