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| | ==Crystal structure of lumiracoxib bound to the apo-mouse-cyclooxygenase-2== | | ==Crystal structure of lumiracoxib bound to the apo-mouse-cyclooxygenase-2== |
| - | <StructureSection load='4oty' size='340' side='right' caption='[[4oty]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='4oty' size='340' side='right'caption='[[4oty]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4oty]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4llz 4llz]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OTY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OTY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4oty]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4llz 4llz]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OTY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OTY 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=LUR:{2-[(2-CHLORO-6-FLUOROPHENYL)AMINO]-5-METHYLPHENYL}ACETIC+ACID'>LUR</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]] 2.354Å</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=LUR:{2-[(2-CHLORO-6-FLUOROPHENYL)AMINO]-5-METHYLPHENYL}ACETIC+ACID'>LUR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4oty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oty OCA], [https://pdbe.org/4oty PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oty RCSB], [https://www.ebi.ac.uk/pdbsum/4oty PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oty 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=4oty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oty OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4oty RCSB], [http://www.ebi.ac.uk/pdbsum/4oty PDBsum]</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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4oty" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Prostaglandin-endoperoxide synthase]] | + | [[Category: Mus musculus]] |
| - | [[Category: Banerjee, S]] | + | [[Category: Banerjee S]] |
| - | [[Category: Marnett, L J]] | + | [[Category: Marnett LJ]] |
| - | [[Category: Windsor, M A]] | + | [[Category: Windsor MA]] |
| - | [[Category: Xu, S]] | + | [[Category: Xu S]] |
| - | [[Category: Drug complex]]
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| - | [[Category: Glycosylation]]
| + | |
| - | [[Category: Heme]]
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| - | [[Category: Monotopic membrane protein]]
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| - | [[Category: Nsaid]]
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| - | [[Category: Oxidoreductase]]
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| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Protein-drug complex]]
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| Structural highlights
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
Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5'-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35A crystal structure of lumiracoxib bound to COX-2.
Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.,Windsor MA, Valk PL, Xu S, Banerjee S, Marnett LJ Bioorg Med Chem Lett. 2013 Nov 1;23(21):5860-5864. doi:, 10.1016/j.bmcl.2013.08.097. Epub 2013 Sep 6. PMID:24060487[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
- ↑ Windsor MA, Valk PL, Xu S, Banerjee S, Marnett LJ. Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5860-5864. doi:, 10.1016/j.bmcl.2013.08.097. Epub 2013 Sep 6. PMID:24060487 doi:http://dx.doi.org/10.1016/j.bmcl.2013.08.097
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