Abstract
PROSTAGLANDINSand glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism1,2. Two isoforms of the membrane protein COX are known3: COX-1, which is constitu-tively expressed in most tissues, is responsible for the physiological production of prostaglandins4; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells5, is responsible for the elevated production of prostaglandins during inflammation6,7. The structure of ovine COX-1 complexed with several NSAIDs has been determined8–10. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 Åresolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Flavonoids as dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and in vitro studies
Beni-Suef University Journal of Basic and Applied Sciences Open Access 23 September 2022
-
Molecular docking prediction and in vitro studies elucidate anti-inflammatory effect of Garcinia extract against inducible nitric oxide synthase and cyclooxygenase-2 targets
Beni-Suef University Journal of Basic and Applied Sciences Open Access 03 March 2022
-
Validating potent anti-inflammatory and anti-rheumatoid properties of Drynaria quercifolia rhizome methanolic extract through in vitro, in vivo, in silico and GC-MS-based profiling
BMC Complementary Medicine and Therapies Open Access 12 March 2021
Access options
Subscribe to Journal
Get full journal access for 1 year
$199.00
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Buy article
Get time limited or full article access on ReadCube.
$32.00
All prices are NET prices.
References
Smith, W. L. & Marnett, L. J. in Metal Ions in Biological Systems (eds Sigel, H. & Sigel, A.) 163–199 (Marcel Dekker, New York, 1994).
Otto, J. C. & Smith, W. L. J. Lipid Mediat. Cell Signal. 12, 139–156 (1995).
Vane, J. R. et al. Proc. Natl Acad. Sci. USA 91, 2046–2050 (1994).
DeWitt, D. L. et al. J. Biol. Chem. 265, 5192–5196 (1990).
Herschman, H. R. Biochim. Biophys. Acta 1299, 125–140 (1996).
Seibert, K. et al. Proc. Natl Acad. Sci. USA 91, 12013–12017 (1994).
Masferrer, J. L. et al. Proc. Natl Acad. Sci. USA 91, 3228–3232 (1994).
Picot, D., Loll, P. J. & Garavito, R. M. Nature 367, 243–249 (1994).
Loll, P. J., Picot, D. & Garavito, R. M. Nature Struct. Biol. 2, 637–643 (1995).
Loll, P. J., Picot, D., Ekabo, O. & Garavito, R. M. Biochemistry 35, 7330–7340 (1996).
Marnett, L. J. & Maddipati, K. R. in Peroxidasesin Chemistry and Biology Vol 1 (eds Everse, K. E. & Grisham, M. B.) 293–334 (CRC Press, Boca Raton, FL, 1991).
Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J. & Vane, J. R. Proc. Natl Acad. Sci. USA 90, 11693–11697 (1993).
Laneuville, O. et al. J. Pharmacol. Exp. Ther. 271, 927–934 (1994).
Gans, K. R. et al. J. Pharmacol. Exp. Ther. 254, 180–187 (1990).
Futaki, N. et al. Prostaglandins 47, 55–59 (1994).
Smith, W. L., Eling, T. E., Kulmacz, R. J., Marnett, L. J. & Tsai, A. Biochemistry 31, 3–7 (1992).
Dietz, R., Nastainczyk, W. & Ruf, H. H. Eur. J. Biochem. 171, 320–327 (1988).
Van, J. R. Nature New. Biol. 231, 232–235 (1971).
Hoogsteen, K. & Trenner, N. R. J. Org. Chem. 35, 521 (1970).
Black, W. C. et al. Bioorg. Med. Chem. Lett. 6, 725–730 (1996).
Gierse, J. K. et al. J. Biol. Chem. 271, 15810–15814 (1996).
Bertenshaw, S. R. et al. Bioorg. Med. Chem. Lett. 5, 2919–2922 (1995).
Kulmacz, R. J. & Lands, W. E. M. J. Biol. Chem. 260, 12572–12578 (1985).
Bhattacharyya, D. K., Lecomte, M., Rieke, C. J., Garavito, R. M. & Smith, W. L. J. Biol. Chem. 271, 2179–2184 (1996).
Copeland, R. A. et al. Proc. Natl Acad. Sci. USA 91, 11202–11206 (1994).
Gierse, J. K. et al. Biochem. J. 305, 479–484 (1995).
Otwinowski, Z. & Minor, W. in Data Collection and Processing (eds Sawyer, L., Isaacs, N. & Bailey, S.) 556–562 (SERC Daresbury Laboratory, Warrington, UK, 1993).
Fitzgerald, P. M. D. J. Appl. Crystallogr. 21, 273–278 (1988).
Brunger, A. T. XPLOR (Version 3.1): A System for X-ray Crystallography and NMR (Yale Univ. Press, New Haven, CT, 1993).
Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgarrd, M. Acta Crystallogr. A47, 110–119 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kurumbail, R., Stevens, A., Gierse, J. et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384, 644–648 (1996). https://doi.org/10.1038/384644a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/384644a0
This article is cited by
-
Novel Benzo[4,5]imidazo[1,2-a]pyrimidine derivatives as selective Cyclooxygenase-2 Inhibitors: Design, synthesis, docking studies, and biological evaluation
Medicinal Chemistry Research (2023)
-
Molecular docking prediction and in vitro studies elucidate anti-inflammatory effect of Garcinia extract against inducible nitric oxide synthase and cyclooxygenase-2 targets
Beni-Suef University Journal of Basic and Applied Sciences (2022)
-
Flavonoids as dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and in vitro studies
Beni-Suef University Journal of Basic and Applied Sciences (2022)
-
Mechanism-Based Pharmacological Treatment for Chronic Non-cancer Pain in Adolescents: Current Approaches and Future Directions
Pediatric Drugs (2022)
-
Synthesis, in vitro and in silico enzyme (COX-1/2 & LOX-5), free radical scavenging and cytotoxicity profiling of the 2,4-dicarbo substituted quinazoline 3-oxides
Medicinal Chemistry Research (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
