title: The structure of ibuprofen bound to cyclooxygenase-2.
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.
authors.affiliation: Department of Structural Biology, The State University of New York at Buffalo and the Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Orlando
authors.affiliation: Department of Structural Biology, The State University of New York at Buffalo and the Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lucido
authors.affiliation: Department of Structural Biology, The State University of New York at Buffalo and the Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA. Electronic address: malkowski@hwi.buffalo.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Malkowski
mesh_terms: D000818:Animals; D003460:Crystallization; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D007052:Ibuprofen / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D051546:Cyclooxygenase 2; D007052:Ibuprofen
keywords: Crystal structure; Cyclooxygenase; Ibuprofen; Nonsteroidal anti-inflammatory drugs; Prostaglandin H(2) synthase