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3tzi, resolution 2.15Å ()
Ligands: , , , , , ,
Gene: Cox-2, Cox2, Pghs-b, Ptgs2, Tis10 (Mus musculus)
Activity: Prostaglandin-endoperoxide synthase, with EC number
Related: 3hs5, 3krk, 3qh0, 3mdl, 1diy, 1cvu

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

X-ray crystal structure of arachidonic acid bound in the cyclooxygenase channel of G533V murine COX-2

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

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

About this Structure

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


  • Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove. J Biol Chem. 2012 May 25. PMID:22637474 doi:10.1074/jbc.M112.372243

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