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4m10

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{{STRUCTURE_4m10| PDB=4m10 | SCENE= }}
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==Crystal Structure of Murine Cyclooxygenase-2 Complex with Isoxicam==
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===Crystal Structure of Murine Cyclooxygenase-2 Complex with Isoxicam===
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<StructureSection load='4m10' size='340' side='right' caption='[[4m10]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24425867}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4m10]] is a 4 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=4M10 OCA]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ICD:4-HYDROXY-2-METHYL-N-(5-METHYL-1,2-OXAZOL-3-YL)-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE+1,1-DIOXIDE'>ICD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m11|4m11]]</td></tr>
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<tr><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>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4m10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m10 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4m10 RCSB], [http://www.ebi.ac.uk/pdbsum/4m10 PDBsum]</span></td></tr>
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<table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Oxicams are widely used non-steroidal anti-inflammatory drugs (NSAIDs), but little is known about the molecular basis of the interaction with their target enzymes, the cyclooxygenases (COX). Isoxicam is a non-selective inhibitor of COX-1 and COX-2 whereas meloxicam displays some selectivity for COX-2. Here we report crystal complexes of COX-2 with isoxicam and meloxicam at 2.0 angstroms and 2.45 angstroms, respectively, and a crystal complex of COX-1 with meloxicam at 2.4 angstroms. These structures reveal that the oxicams bind to the active site of COX-2 using a binding pose not seen with other NSAIDs through two highly coordinated water molecules. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding and the heteroatom of the carboxamide ring of the oxicam scaffold interacts with Tyr-385 and Ser-530 through a highly coordinated water molecule. The nitrogen atom of the thiazine and the oxygen atom of the carboxamide bind to Arg-120 and Tyr-355 via another highly ordered water molecule. The rotation of Leu-531 in the structure opens a novel-binding pocket, which is not utilized for the binding of other NSAIDs. In addition, a detailed study of meloxicam-COX-2 interactions revealed that mutation of Val-434 to Ile significantly reduces inhibition by meloxicam due to subtle changes around Phe-518, giving rise to the preferential inhibition of COX-2 over COX-1.
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==Function==
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Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network.,Xu S, Hermanson DJ, Banerjee S, Ghebreselasie K, Clayton GM, Garavito RM, Marnett LJ J Biol Chem. 2014 Jan 14. PMID:24425867<ref>PMID:24425867</ref>
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[[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>
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==About this Structure==
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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[[4m10]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M10 OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:024425867</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
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[[Category: Lk3 transgenic mice]]
[[Category: Prostaglandin-endoperoxide synthase]]
[[Category: Prostaglandin-endoperoxide synthase]]
[[Category: Banerjee, S.]]
[[Category: Banerjee, S.]]

Revision as of 06:45, 14 May 2014

Crystal Structure of Murine Cyclooxygenase-2 Complex with Isoxicam

4m10, resolution 2.01Å

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