title: Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.
abstract: Prostaglandins and 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 metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. 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 A resolution. 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.
authors.affiliation: G.D. Searle, St Louis, Missouri 63198, USA. rgkuru@punchiri.monsanto.com
authors.forename: R G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: A M
authors.initials: AM
authors.lastname: Stevens
authors.forename: J K
authors.initials: JK
authors.lastname: Gierse
authors.forename: J J
authors.initials: JJ
authors.lastname: McDonald
authors.forename: R A
authors.initials: RA
authors.lastname: Stegeman
authors.forename: J Y
authors.initials: JY
authors.lastname: Pak
authors.forename: D
authors.initials: D
authors.lastname: Gildehaus
authors.forename: J M
authors.initials: JM
authors.lastname: Miyashiro
authors.forename: T D
authors.initials: TD
authors.lastname: Penning
authors.forename: K
authors.initials: K
authors.lastname: Seibert
authors.forename: P C
authors.initials: PC
authors.lastname: Isakson
authors.forename: W C
authors.initials: WC
authors.lastname: Stallings
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005480:Flurbiprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D011487:Protein Conformation; D011720:Pyrazoles / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; C102643:SC 558; D005480:Flurbiprofen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin