The structure of ibuprofen bound to cyclooxygenase-2

J Struct Biol. 2015 Jan;189(1):62-6. doi: 10.1016/j.jsb.2014.11.005. Epub 2014 Nov 25.


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.

Keywords: Crystal structure; Cyclooxygenase; Ibuprofen; Nonsteroidal anti-inflammatory drugs; Prostaglandin H(2) synthase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Crystallization
  • Cyclooxygenase 2 / chemistry*
  • Ibuprofen / chemistry*
  • Mice
  • Models, Molecular*
  • Protein Conformation


  • Cyclooxygenase 2
  • Ibuprofen