The structure of NS-398 bound to cyclooxygenase-2

• Published in: Journal of structural biology Vol. 176; no. 2; pp. 254 - 258
• Main Authors: Vecchio, Alex J., Malkowski, Michael G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2011
• Subjects: Amino Acid Motifs; Animals; Binding Sites; Crystallography, X-Ray; Cyclooxygenase; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 Inhibitors - chemistry; Hydrogen Bonding; Mice; Models, Molecular; Nitrobenzenes - chemistry; Nonsteroidal anti-inflammatory drugs; NS-398; Prostaglandin H 2 synthase; Protein Binding; Protein Structure, Tertiary; Sulfonamides - chemistry; X-ray crystal structure; AA; MR; ov; βOG; mu; NS-398; X-ray crystal structure; COX; hu; Cyclooxygenase; Prostaglandin H 2 synthase; NSAIDs; Nonsteroidal anti-inflammatory drugs
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1016/j.jsb.2011.07.019

The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate prostaglandin H
2 from arachidonic acid (AA) in the committed step of prostaglandin biogenesis and are the targets for nonsteroidal anti-inflammatory drugs (NSAIDs). N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) was the first in a series of isoform-selective drugs designed to preferentially inhibit COX-2, with the aim of ameliorating many of the toxic gastrointestinal side effects caused by conventional NSAID inhibition. We determined the X-ray crystal structure of murine COX-2 in complex with NS-398 utilizing synchrotron radiation to 3.0
A resolution. NS-398 binds in the cyclooxygenase channel in a conformation that is different than that observed for other COX-2-selective inhibitors, such as celecoxib, with no discernible penetration into the side pocket formed in COX-2 by the isoform-specific substitutions of I434V, H513R, and I523V. Instead, the methanesulfonamide moiety of NS-398 interacts with the side chain of Arg-120 at the opening of the cyclooxygenase channel, similar to that observed for acidic, nonselective NSAIDs such as indomethacin and flurbiprofen. Our structure validates inhibitor studies that identified Arg-120 as a molecular determinant for time-dependent inhibition of COX-2 by NS-398.