3RR3

Structure of (R)-flurbiprofen bound to mCOX-2

Summary for 3RR3

• Entry DOI: 10.2210/pdb3rr3/pdb
• Descriptor: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: flurbiprofen, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 4
• Total formula weight: 266085.86

Authors

Duggan, K.C.,Hermanson, D.J.,Musee, J.,Prusakiewicz, J.J.,Scheib, J.,Carter, B.D.,Banerjee, S.,Oates, J.A.,Marnett, L.J. (deposition date: 2011-04-28, release date: 2011-11-09, Last modification date: 2024-10-09)

Primary citation

Duggan, K.C.,Hermanson, D.J.,Musee, J.,Prusakiewicz, J.J.,Scheib, J.L.,Carter, B.D.,Banerjee, S.,Oates, J.A.,Marnett, L.J.
(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.
Nat.Chem.Biol., 7:803-809, 2011

PubMed Abstract: Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation. Crystal structures of the COX-2–(R)-naproxen and COX-2–(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R) enantiomers relative to (S) enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells. Substrate-selective inhibition provides new tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain.

PubMed: 22053353
DOI: 10.1038/nchembio.663

Experimental method

X-RAY DIFFRACTION (2.842 Å)