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| | ==The Structure of Mefenamic Acid Bound to Human Cyclooxygenase-2== | | ==The Structure of Mefenamic Acid Bound to Human Cyclooxygenase-2== |
| - | <StructureSection load='5ikr' size='340' side='right' caption='[[5ikr]], [[Resolution|resolution]] 2.34Å' scene=''> | + | <StructureSection load='5ikr' size='340' side='right'caption='[[5ikr]], [[Resolution|resolution]] 2.34Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ikr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IKR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ikr]] 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=5IKR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IKR 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=COH:PROTOPORPHYRIN+IX+CONTAINING+CO'>COH</scene>, <scene name='pdbligand=ID8:2-[(2,3-DIMETHYLPHENYL)AMINO]BENZOIC+ACID'>ID8</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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]] 2.342Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ikt|5ikt]], [[5ikq|5ikq]], [[5ikv|5ikv]]</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=ID8:2-[(2,3-DIMETHYLPHENYL)AMINO]BENZOIC+ACID'>ID8</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</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=5ikr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ikr OCA], [https://pdbe.org/5ikr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ikr RCSB], [https://www.ebi.ac.uk/pdbsum/5ikr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ikr 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=5ikr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ikr OCA], [http://pdbe.org/5ikr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ikr RCSB], [http://www.ebi.ac.uk/pdbsum/5ikr PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PGH2_HUMAN PGH2_HUMAN]] Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.<ref>PMID:16373578</ref> | + | [https://www.uniprot.org/uniprot/PGH2_HUMAN PGH2_HUMAN] Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.<ref>PMID:16373578</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5ikr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ikr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Prostaglandin-endoperoxide synthase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Malkowski, M G]] | + | [[Category: Large Structures]] |
| - | [[Category: Orlando, B J]] | + | [[Category: Malkowski MG]] |
| - | [[Category: Cox mefenamic]] | + | [[Category: Orlando BJ]] |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
5ikr is a 2 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 2.342Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
PGH2_HUMAN Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.[1]
Publication Abstract from PubMed
Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid (AA) and endocannabinoid substrates, placing the enzyme at a unique junction between the eicosanoid and endocannabinoid signaling pathways. COX-2 is a sequence homodimer, but the enzyme displays half-of-sites reactivity, such that only one monomer of the dimer is active at a given time. Certain rapid reversible, competitive nonsterroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit COX-2 in a substrate-selective manner, with the binding of inhibitor to a single monomer sufficient to inhibit the oxygenation of endocannabinoids, but not AA. The underlying mechanism responsible for substrate-selective inhibition has remained elusive. We utilized structural and biophysical methods to evaluate flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid for their ability to act as substrate-selective inhibitors. Crystal structures of each drug in complex with human COX-2 revealed that the inhibitor binds within the cyclooxygenase channel in an inverted orientation, with the carboxylate group interacting with Tyr-385 and Ser-530 at the top of the channel. Tryptophan fluorescence quenching, continuous-wave electron spin resonance, and UV/Vis spectroscopy demonstrate that flufenamic acid, mefenamic acid, and tolfenamic acid are substrate-selective inhibitors that bind rapidly to COX-2, quench tyrosyl radicals, and reduce higher oxidation states of the heme moiety. Substrate-selective inhibition was attenuated by the addition of the lipid peroxide 15-hydroperoxyeicosatertaenoic acid. Collectively, these studies implicate peroxide tone as an important mechanistic component of substrate-selective inhibition by flufenamic acid, mefenamic acid, and tolfenamic acid.
Substrate Selective Inhibition of Cyclooxygenase-2 by Fenamic Acid Derivatives is Dependent on Peroxide Tone.,Orlando BJ, Malkowski MG J Biol Chem. 2016 May 20. pii: jbc.M116.725713. PMID:27226593[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005 Dec 23;310(5756):1966-70. PMID:16373578 doi:http://dx.doi.org/10.1126/science.1119407
- ↑ Orlando BJ, Malkowski MG. Substrate Selective Inhibition of Cyclooxygenase-2 by Fenamic Acid Derivatives is Dependent on Peroxide Tone. J Biol Chem. 2016 May 20. pii: jbc.M116.725713. PMID:27226593 doi:http://dx.doi.org/10.1074/jbc.M116.725713
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