View source for 9pfl


==Crystal structure of human 15-PGDH in complex with small molecule compound 1==
<StructureSection load='9pfl' size='340' side='right'caption='[[9pfl]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9pfl]] is a 2 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=9PFL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PFL 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]] 1.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CH2:(4S)-7-[7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one'>A1CH2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=9pfl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pfl OCA], [https://pdbe.org/9pfl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pfl RCSB], [https://www.ebi.ac.uk/pdbsum/9pfl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pfl ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PGDH_HUMAN PGDH_HUMAN] Defects in HPGD are the cause of hypertrophic osteoarthropathy, primary, autosomal recessive, type 1 (PHOAR1) [MIM:[https://omim.org/entry/259100 259100]. A disease characterized by digital clubbing, periostosis, acroosteolysis, painful joint enlargement, and variable features of pachydermia that include thickened facial skin and a thickened scalp. Other developmental anomalies include delayed closure of the cranial sutures and congenital heart disease.<ref>PMID:18500342</ref>   Defects in HPGD are the cause of cranioosteoarthropathy (COA) [MIM:[https://omim.org/entry/259100 259100]. A form of osterarthropathy characterized by swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia is not a prominent feature.<ref>PMID:18500342</ref>   Defects in HPGD are a cause of isolated congenital nail clubbing (ICNC) [MIM:[https://omim.org/entry/119900 119900]; also called clubbing of digits or hereditary acropachy. ICNC is a rare genodermatosis characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx. It is usually symmetrical and bilateral (in some cases unilateral). In nail clubbing usually the distal end of the nail matrix is relatively high compared to the proximal end, while the nail plate is complete but its dimensions and diameter more or less vary in comparison to normal. There may be different fingers and toes involved to varying degrees. Some fingers or toes are spared, but the thumbs are almost always involved.<ref>PMID:18805827</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PGDH_HUMAN PGDH_HUMAN] Prostaglandin inactivation. Contributes to the regulation of events that are under the control of prostaglandin levels. Catalyzes the NAD-dependent dehydrogenation of lipoxin A4 to form 15-oxo-lipoxin A4. Inhibits in vivo proliferation of colon cancer cells.<ref>PMID:10837478</ref> <ref>PMID:15574495</ref> <ref>PMID:16828555</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
PGE2 plays important roles in immune cell function and in potentiating tissue regeneration. 15-PGDH is the key enzyme involved in inactivation of PGE2 and its inhibition therefore provides valuable therapeutic opportunity. We have solved the first cocrystal structure of 15-PGDH bound to small molecule inhibitors, enabling us to efficiently investigate and understand the key functionalities required for potency. Rational structure-based design coupled with a host of advanced computational methods, including FEP+ and WaterMap, were used to develop novel series of 15-PGDH inhibitors. Of note, a machine-learning (ML) model trained with potencies predicted by FEP+ yielded a powerful tool to guide synthetic priority across a large virtual chemical library. Ultimately, a lead compound demonstrated elevation of colonic PGE2 following IP administration in mice, consistent with our therapeutic hypothesis.

Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors.,Dodda LS, Campos S, Ciccone D, Carreiro S, Leit S, Brennan D, Zephyr J, Jacques-O'Hagan S, Kumar S, Kuo FS, Shaik MM, Price DJ, Loh C, Edmondson SD, Tummino P, Kaila N J Med Chem. 2025 Aug 27. doi: 10.1021/acs.jmedchem.5c01231. PMID:40864846<ref>PMID:40864846</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9pfl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brennan D]]
[[Category: Shaik MM]]