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==X-ray crystal structure of 1-arachidonoyl glycerol bound to the cyclooxygenase channel of cyclooxygenase-2== | ==X-ray crystal structure of 1-arachidonoyl glycerol bound to the cyclooxygenase channel of cyclooxygenase-2== | ||
<StructureSection load='3mdl' size='340' side='right' caption='[[3mdl]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='3mdl' size='340' side='right'caption='[[3mdl]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3mdl]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3mdl]] is a 2 chain structure with sequence from [https://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=3MDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MDL FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1AG:(2S)-2,3-DIHYDROXYPROPYL+(5Z,8Z,11Z,14Z)-ICOSA-5,8,11,14-TETRAENOATE'>1AG</scene>, <scene name='pdbligand=AKR:ACRYLIC+ACID'>AKR</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=COH:PROTOPORPHYRIN+IX+CONTAINING+CO'>COH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand= | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1AG:(2S)-2,3-DIHYDROXYPROPYL+(5Z,8Z,11Z,14Z)-ICOSA-5,8,11,14-TETRAENOATE'>1AG</scene>, <scene name='pdbligand=AKR:ACRYLIC+ACID'>AKR</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=COH:PROTOPORPHYRIN+IX+CONTAINING+CO'>COH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hs5|3hs5]], [[3hs6|3hs6]], [[3hs7|3hs7]], [[3krk|3krk]], [[1diy|1diy]], [[1cvu|1cvu]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3hs5|3hs5]], [[3hs6|3hs6]], [[3hs7|3hs7]], [[3krk|3krk]], [[1diy|1diy]], [[1cvu|1cvu]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mdl OCA], [https://pdbe.org/3mdl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mdl RCSB], [https://www.ebi.ac.uk/pdbsum/3mdl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mdl ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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> | ||
<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 3mdl" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3mdl" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Lk3 transgenic mice]] | [[Category: Lk3 transgenic mice]] | ||
[[Category: Prostaglandin-endoperoxide synthase]] | [[Category: Prostaglandin-endoperoxide synthase]] | ||
Revision as of 08:39, 6 October 2021
X-ray crystal structure of 1-arachidonoyl glycerol bound to the cyclooxygenase channel of cyclooxygenase-2X-ray crystal structure of 1-arachidonoyl glycerol bound to the cyclooxygenase channel of cyclooxygenase-2
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 PubMedThe cyclooxygenases (COX-1 and COX-2) oxygenate arachidonic acid (AA) in the committed step of prostaglandin biogenesis. Substitutions of I434V, H513R, and I523V constitute the only differences in residues lining the cyclooxygenase channel between COX-1 and COX-2. These changes create a hydrophobic pocket in COX-2, with Arg-513 located at the base of the pocket, which has been exploited in the design of COX-2-selective inhibitors. Previous studies have shown that COX-2, but not COX-1, can oxygenate endocannabinoid substrates, including 2-arachidonoyl glycerol (2-AG). To investigate the isoform-specific structural basis of endocannabinoid binding to COX-2, we determined the crystal structure of the 2-AG isomer 1-arachidonoyl glycerol (1-AG) in complex with wild type and R513H murine (mu) COX-2 to 2.2 and 2.35 A, respectively, and R513H muCOX-2 in complex with AA to 2.45 A resolution. The 2,3-dihydroxypropyl moiety of 1-AG binds near the opening of the cyclooxygenase channel in the space vacated by the movement of the Leu-531 side chain, validating our previous hypothesis implicating the flexibility of the Leu-531 side chain as a determinant for the ability of COX-2 to oxygenate endocannabinoid substrates. Functional analyses carried out to compliment our structural findings indicated that Y355F and R513H muCOX-2 constructs had no effect on the oxygenation of 1-AG and 2-AG, whereas substitutions that resulted in a shortened side chain for Leu-531 had only modest effects. Both AA and 1-AG bind to R513H muCOX-2 in conformations similar to those observed in the co-crystal structures of these substrates with wild type enzyme. The structural basis of endocannabinoid oxygenation by cyclooxygenase-2.,Vecchio AJ, Malkowski MG J Biol Chem. 2011 Jun 10;286(23):20736-45. Epub 2011 Apr 13. PMID:21489986[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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