3NT1

High resolution structure of naproxen:COX-2 complex.

Summary for 3NT1

• Entry DOI: 10.2210/pdb3nt1/pdb
• Related: 1CQE 1PXX 3NTB 3PGH
• Descriptor: Prostaglandin-endoperoxide synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: prostaglandin h2 synthase, cyclooxygenase-2, naproxen, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 2
• Total formula weight: 139332.93

Authors

Duggan, K.C.,Musee, J.,Walters, M.J.,Harp, J.M.,Kiefer, J.R.,Oates, J.A.,Marnett, L.J. (deposition date: 2010-07-02, release date: 2010-09-01, Last modification date: 2023-12-27)

Primary citation

Duggan, K.C.,Walters, M.J.,Musee, J.,Harp, J.M.,Kiefer, J.R.,Oates, J.A.,Marnett, L.J.
Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen.
J.Biol.Chem., 285:34950-34959, 2010

PubMed Abstract: Naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions are tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH(2) for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 Å resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.

PubMed: 20810665
DOI: 10.1074/jbc.M110.162982

Experimental method

X-RAY DIFFRACTION (1.73 Å)