9pfm

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human 15-PGDH in complex with small molecule compound 8b

Structural highlights

9pfm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.88Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PGDH_HUMAN Defects in HPGD are the cause of hypertrophic osteoarthropathy, primary, autosomal recessive, type 1 (PHOAR1) [MIM: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.^[1] Defects in HPGD are the cause of cranioosteoarthropathy (COA) [MIM: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.^[2] Defects in HPGD are a cause of isolated congenital nail clubbing (ICNC) [MIM: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.^[3]

Function

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.^[4] ^[5] ^[6]

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^[7]

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

References

↑ Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25. PMID:18500342 doi:10.1038/ng.153
↑ Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25. PMID:18500342 doi:10.1038/ng.153
↑ Tariq M, Azeem Z, Ali G, Chishti MS, Ahmad W. Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet. 2009 Jan;46(1):14-20. doi: 10.1136/jmg.2008.061234. Epub 2008 Sep, 19. PMID:18805827 doi:10.1136/jmg.2008.061234
↑ Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J Biol Chem. 2000 Aug 18;275(33):25372-80. PMID:10837478 doi:10.1074/jbc.M002863200
↑ Yan M, Rerko RM, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson JK, Luo G, Hensold J, Tai HH, Wilson K, Markowitz SD. 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17468-73. Epub 2004 Dec 1. PMID:15574495 doi:10.1073/pnas.0406142101
↑ Cho H, Huang L, Hamza A, Gao D, Zhan CG, Tai HH. Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2. Bioorg Med Chem. 2006 Oct 1;14(19):6486-91. Epub 2006 Jul 7. PMID:16828555 doi:10.1016/j.bmc.2006.06.030
↑ 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. Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors. J Med Chem. 2025 Aug 27. PMID:40864846 doi:10.1021/acs.jmedchem.5c01231

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9pfm"

Categories: Homo sapiens | Large Structures | Brennan D | Shaik MM

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[9pfm]] 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=9PFM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PFM 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]] 1.88&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=SWL:2-[butyl(oxidanyl)-$l^{4}-sulfanyl]-4-(2,3-dimethylimidazol-4-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine'>SWL</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=SWL:2-[(S)-butyl(hydroxy)-lambda~4~-sulfanyl]-4-(1,2-dimethyl-1H-imidazol-5-yl)-6-(1,3-thiazol-2-yl)thieno[2,3-b]pyridin-3-amine'>SWL</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=9pfm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pfm OCA], [https://pdbe.org/9pfm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pfm RCSB], [https://www.ebi.ac.uk/pdbsum/9pfm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pfm ProSAT]</span></td></tr>
 </table>

9pfm

From Proteopedia

Current revision

Crystal structure of human 15-PGDH in complex with small molecule compound 8b

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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