4PH9

The structure of Ibuprofen bound to cyclooxygenase-2

Summary for 4PH9

• Entry DOI: 10.2210/pdb4ph9/pdb
• Related: 1EQG 3HS5 3NT1 3QMO
• Descriptor: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: membrane protein, cyclooxygenase, cox, cox-2, ibuprofen, monotopic, prostaglandin, nsaid, oxidoreductase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 132637.56

Authors

Orlando, B.J.,Lucido, M.J.,Malkowski, M.G. (deposition date: 2014-05-05, release date: 2014-11-26, Last modification date: 2024-10-23)

Primary citation

Orlando, B.J.,Lucido, M.J.,Malkowski, M.G.
The structure of ibuprofen bound to cyclooxygenase-2.
J.Struct.Biol., 189:62-66, 2015

PubMed Abstract: The cyclooxygenases (COX-1 and COX-2) catalyze the rate-limiting step in the biosynthesis of prostaglandins, and are the pharmacological targets of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors (coxibs). Ibuprofen (IBP) is one of the most commonly available over-the-counter pharmaceuticals in the world. The anti-inflammatory and analgesic properties of IBP are thought to arise from inhibition of COX-2 rather than COX-1. While an X-ray crystal structure of IBP bound to COX-1 has been solved, no such structure exists for the cognate isoform COX-2. We have determined the crystal structure of muCOX-2 with a racemic mixture of (R/S)-IBP. Our structure reveals that only the S-isomer of IBP was bound, indicating that the S-isomer possesses higher affinity for COX-2 than the R-isomer. Mutational analysis of Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel confirmed their role in binding and inhibition of COX-2 by IBP. Our results provide the first atomic level detail of the interaction between IBP and COX-2.

PubMed: 25463020
DOI: 10.1016/j.jsb.2014.11.005

Experimental method

X-RAY DIFFRACTION (1.81 Å)