|
|
| (14 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:3pgh.gif|left|200px]]<br /><applet load="3pgh" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="3pgh, resolution 2.5Å" /> | |
| - | '''CYCLOOXYGENASE-2 (PROSTAGLANDIN SYNTHASE-2) COMPLEXED WITH A NON-SELECTIVE INHIBITOR, FLURBIPROFEN'''<br /> | |
| | | | |
| - | ==Overview== | + | ==CYCLOOXYGENASE-2 (PROSTAGLANDIN SYNTHASE-2) COMPLEXED WITH A NON-SELECTIVE INHIBITOR, FLURBIPROFEN== |
| - | Prostaglandins and glucocorticoids are potent mediators of inflammation., Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by, inhibition of prostaglandin production. The pharmacological target of, NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which, catalyses the first committed step in arachidonic-acid metabolism. Two, isoforms of the membrane protein COX are known: COX-1, which is, constitutively expressed in most tissues, is responsible for the, physiological production of prostaglandins; and COX-2, which is induced by, cytokines, mitogens and endotoxins in inflammatory cells, is responsible, for the elevated production of prostaglandins during inflammation. The, structure of ovine COX-1 complexed with several NSAIDs has been, determined. Here we report the structures of unliganded murine COX-2 and, complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2, inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain, the structural basis for the selective inhibition of COX-2, and, demonstrate some of the conformational changes associated with, time-dependent inhibition. | + | <StructureSection load='3pgh' size='340' side='right'caption='[[3pgh]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[3pgh]] is a 4 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=3PGH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PGH 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]] 2.5Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLP:FLURBIPROFEN'>FLP</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=3pgh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pgh OCA], [https://pdbe.org/3pgh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pgh RCSB], [https://www.ebi.ac.uk/pdbsum/3pgh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pgh ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pg/3pgh_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3pgh ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Prostaglandins and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition. |
| | | | |
| - | ==About this Structure==
| + | Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.,Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC Nature. 1996 Dec 19-26;384(6610):644-8. PMID:8967954<ref>PMID:8967954</ref> |
| - | 3PGH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with NAG, HEM and FLP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <scene name='pdbsite=ACE:SER 530 Is Acetylated By Aspirin (An Acetyl Group Is Cov ...'>ACE</scene>, <scene name='pdbsite=CAT:TYR 385 Is Believed To Be The Amino Acid That Abstracts ...'>CAT</scene>, <scene name='pdbsite=HEM:HIS 388 Is The Axial Ligand To The Heme'>HEM</scene> and <scene name='pdbsite=SUB:ARG 120 Is Believed To Anchor The Carboxylate Of Substra ...'>SUB</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=3PGH OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents., Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC, Nature. 1996 Dec 19-26;384(6610):644-8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8967954 8967954]
| + | </div> |
| - | [[Category: Mus musculus]]
| + | <div class="pdbe-citations 3pgh" style="background-color:#fffaf0;"></div> |
| - | [[Category: Prostaglandin-endoperoxide synthase]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Kurumbail, R.]]
| + | |
| - | [[Category: Stallings, W.]]
| + | |
| - | [[Category: FLP]]
| + | |
| - | [[Category: HEM]]
| + | |
| - | [[Category: NAG]]
| + | |
| - | [[Category: arthritis]]
| + | |
| - | [[Category: cyclooxygenase]]
| + | |
| - | [[Category: dioxygenase]]
| + | |
| - | [[Category: inflammation]]
| + | |
| - | [[Category: nonsteroidal antiinflammatory drugs]]
| + | |
| - | [[Category: oxidoreductase]]
| + | |
| - | [[Category: peroxidase]]
| + | |
| - | [[Category: prostaglandin]]
| + | |
| - | [[Category: prostaglandin synthase]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 20:41:37 2007''
| + | ==See Also== |
| | + | *[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Mus musculus]] |
| | + | [[Category: Kurumbail R]] |
| | + | [[Category: Stallings W]] |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Prostaglandins and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.
Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.,Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC Nature. 1996 Dec 19-26;384(6610):644-8. PMID:8967954[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
- ↑ Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996 Dec 19-26;384(6610):644-8. PMID:8967954 doi:http://dx.doi.org/10.1038/384644a0
|
