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| | <StructureSection load='5w58' size='340' side='right'caption='[[5w58]], [[Resolution|resolution]] 2.27Å' scene=''> | | <StructureSection load='5w58' size='340' side='right'caption='[[5w58]], [[Resolution|resolution]] 2.27Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5w58]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W58 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W58 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5w58]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W58 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W58 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=FF8:(2S)-2-{2-fluoro-3-[(hexylcarbamoyl)oxy][1,1-biphenyl]-4-yl}propanoic+acid'>FF8</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.267Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=FF8:(2S)-2-{2-fluoro-3-[(hexylcarbamoyl)oxy][1,1-biphenyl]-4-yl}propanoic+acid'>FF8</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PRD_900017:triacetyl-beta-chitotriose'>PRD_900017</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] </span></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=5w58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w58 OCA], [https://pdbe.org/5w58 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w58 RCSB], [https://www.ebi.ac.uk/pdbsum/5w58 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w58 ProSAT]</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=5w58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w58 OCA], [http://pdbe.org/5w58 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w58 RCSB], [http://www.ebi.ac.uk/pdbsum/5w58 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w58 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PGH2_MOUSE PGH2_MOUSE]] Mediates the formation of prostaglandins from arachidonate. May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity.<ref>PMID:12925531</ref> <ref>PMID:20463020</ref> <ref>PMID:20810665</ref> <ref>PMID:21489986</ref> | + | [https://www.uniprot.org/uniprot/PGH2_MOUSE PGH2_MOUSE] Mediates the formation of prostaglandins from arachidonate. May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity.<ref>PMID:12925531</ref> <ref>PMID:20463020</ref> <ref>PMID:20810665</ref> <ref>PMID:21489986</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Prostaglandin-endoperoxide synthase]]
| + | [[Category: Banerjee S]] |
| - | [[Category: Banerjee, S]] | + | [[Category: Goodman MC]] |
| - | [[Category: Goodman, M C]] | + | [[Category: Marnett LJ]] |
| - | [[Category: Marnett, L J]] | + | [[Category: Piomelli D]] |
| - | [[Category: Piomelli, D]] | + | [[Category: Xu S]] |
| - | [[Category: Xu, S]] | + | |
| - | [[Category: Cyclooxygenase]]
| + | |
| - | [[Category: Faah-cox dual inhibition]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-inhibitor complex]]
| + | |
| - | [[Category: Prostaglandin]]
| + | |
| - | [[Category: Protein-inhibitor complex]]
| + | |
| Structural highlights
5w58 is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.267Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
PGH2_MOUSE Mediates the formation of prostaglandins from arachidonate. May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity.[1] [2] [3] [4]
Publication Abstract from PubMed
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H2 (PGH2). COX-2 also oxygenates the endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA), to the corresponding PGH2 analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27 A resolution X-ray crystal structure of the COX-2.(S)-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the alpha-methyl group. Thus, (S)-ARN2508 is more potent than (R)-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to (R)-flurbiprofen, (R)-ARN2508 exhibits substrate-selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for (S)-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared to that of (S)-flurbiprofen.
Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.,Goodman MC, Xu S, Rouzer CA, Banerjee S, Ghebreselasie K, Migliore M, Piomelli D, Marnett LJ J Biol Chem. 2018 Jan 11. pii: M117.802058. doi: 10.1074/jbc.M117.802058. PMID:29326169[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem. 2003 Nov 14;278(46):45763-9. Epub 2003 Aug 18. PMID:12925531 doi:http://dx.doi.org/10.1074/jbc.M305481200
- ↑ Vecchio AJ, Simmons DM, Malkowski MG. Structural basis of fatty acid substrate binding to cyclooxygenase-2. J Biol Chem. 2010 Jul 16;285(29):22152-63. Epub 2010 May 12. PMID:20463020 doi:10.1074/jbc.M110.119867
- ↑ Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, Marnett LJ. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. J Biol Chem. 2010 Nov 5;285(45):34950-9. Epub 2010 Sep 1. PMID:20810665 doi:10.1074/jbc.M110.162982
- ↑ Vecchio AJ, Malkowski MG. The structural basis of endocannabinoid oxygenation by cyclooxygenase-2. J Biol Chem. 2011 Jun 10;286(23):20736-45. Epub 2011 Apr 13. PMID:21489986 doi:10.1074/jbc.M111.230367
- ↑ Goodman MC, Xu S, Rouzer CA, Banerjee S, Ghebreselasie K, Migliore M, Piomelli D, Marnett LJ. Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site. J Biol Chem. 2018 Jan 11. pii: M117.802058. doi: 10.1074/jbc.M117.802058. PMID:29326169 doi:http://dx.doi.org/10.1074/jbc.M117.802058
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