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3mdl

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3mdl, resolution 2.20Å ()
Ligands: , , , , , ,
Gene: Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 (Mus musculus)
Activity: Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1
Related: 3hs5, 3hs6, 3hs7, 3krk, 1diy, 1cvu


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

X-ray crystal structure of 1-arachidonoyl glycerol bound to the cyclooxygenase channel of cyclooxygenase-2

Publication Abstract from PubMed

The 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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

3mdl is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA.

See Also

Reference

  • 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

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