4e1g: Difference between revisions
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==X-ray crystal structure of alpha-linolenic acid bound to the cyclooxygenase channel of cyclooxygenase-2== | |||
<StructureSection load='4e1g' size='340' side='right'caption='[[4e1g]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4e1g]] is a 2 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=4E1G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E1G 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKR:ACRYLIC+ACID'>AKR</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LNL:ALPHA-LINOLENIC+ACID'>LNL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</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=4e1g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e1g OCA], [https://pdbe.org/4e1g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e1g RCSB], [https://www.ebi.ac.uk/pdbsum/4e1g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e1g 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The cyclooxygenases (COX-1 and COX-2) generate prostaglandin H(2) from arachidonic acid (AA). In its catalytically productive conformation, AA binds within the cyclooxygenase channel with its carboxylate near Arg-120 and Tyr-355 and omega-end located within a hydrophobic groove above Ser-530. While AA is the preferred substrate for both isoforms, COX-2 can oxygenate a broad spectrum of substrates. Mutational analyses have established that an interaction of the carboxylate of AA with Arg-120 is required for high-affinity binding by COX-1, but not COX-2, suggesting that hydrophobic interactions between the omega-end of substrates and cyclooxygenase channel residues play a significant role in COX-2-mediated oxygenation. We used structure-function analyses to investigate the role that Arg-120 and residues lining the hydrophobic groove play in the binding and oxygenation of substrates by murine (mu) COX-2. Mutations to individual amino acids within the hydrophobic groove exhibited decreased rates of oxygenation towards AA, with little effect on binding. R120A muCOX-2 oxygenated 18-carbon omega-6 and omega-3 substrates, albeit at reduced rates, indicating that an interaction with Arg-120 is not required for catalysis. Structural determinations of Co(3+)-protoporphyrin IX reconstituted muCOX-2 with alpha-linolenic acid and G533V muCOX-2 with AA indicate that proper bis-allylic carbon alignment is the major determinant for efficient substrate oxygenation by COX-2. Overall, these findings implicate Arg-120 and hydrophobic groove residues as determinants that govern proper alignment of the bis-allylic carbon below Tyr-385 for catalysis in COX-2 and confirms nuances between COX isoforms that explain substrate promiscuity. | |||
Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.,Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG J Biol Chem. 2012 May 25. PMID:22637474<ref>PMID:22637474</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4e1g" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Malkowski MG]] | |||
[[Category: Vecchio AJ]] | |||
Latest revision as of 09:55, 27 November 2024
X-ray crystal structure of alpha-linolenic acid bound to the cyclooxygenase channel of cyclooxygenase-2X-ray crystal structure of alpha-linolenic acid bound to the cyclooxygenase channel of cyclooxygenase-2
Structural highlights
FunctionPGH2_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) generate prostaglandin H(2) from arachidonic acid (AA). In its catalytically productive conformation, AA binds within the cyclooxygenase channel with its carboxylate near Arg-120 and Tyr-355 and omega-end located within a hydrophobic groove above Ser-530. While AA is the preferred substrate for both isoforms, COX-2 can oxygenate a broad spectrum of substrates. Mutational analyses have established that an interaction of the carboxylate of AA with Arg-120 is required for high-affinity binding by COX-1, but not COX-2, suggesting that hydrophobic interactions between the omega-end of substrates and cyclooxygenase channel residues play a significant role in COX-2-mediated oxygenation. We used structure-function analyses to investigate the role that Arg-120 and residues lining the hydrophobic groove play in the binding and oxygenation of substrates by murine (mu) COX-2. Mutations to individual amino acids within the hydrophobic groove exhibited decreased rates of oxygenation towards AA, with little effect on binding. R120A muCOX-2 oxygenated 18-carbon omega-6 and omega-3 substrates, albeit at reduced rates, indicating that an interaction with Arg-120 is not required for catalysis. Structural determinations of Co(3+)-protoporphyrin IX reconstituted muCOX-2 with alpha-linolenic acid and G533V muCOX-2 with AA indicate that proper bis-allylic carbon alignment is the major determinant for efficient substrate oxygenation by COX-2. Overall, these findings implicate Arg-120 and hydrophobic groove residues as determinants that govern proper alignment of the bis-allylic carbon below Tyr-385 for catalysis in COX-2 and confirms nuances between COX isoforms that explain substrate promiscuity. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.,Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG J Biol Chem. 2012 May 25. PMID:22637474[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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