STRUCTURAL BASIS FOR SELECTIVE-INHIBITION OF CYCLOOXYGENASE-2 BY ANTIINFLAMMATORY AGENTS

Citation
Rg. Kurumbail et al., STRUCTURAL BASIS FOR SELECTIVE-INHIBITION OF CYCLOOXYGENASE-2 BY ANTIINFLAMMATORY AGENTS, Nature, 384(6610), 1996, pp. 644-648
Citations number
30
Categorie Soggetti
Multidisciplinary Sciences
Journal title
NatureACNP
ISSN journal
00280836
Volume
384
Issue
6610
Year of publication
1996
Pages
644 - 648
Database
ISI
SICI code
0028-0836(1996)384:6610<644:SBFSOC>2.0.ZU;2-V
Abstract
PROSTAGLANDINS and glucocorticoids are potent mediators of inflammatio n. 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 c atalyses the first committed step in arachidonic-acid metabolism(1,2). Two isoforms of the membrane protein COX are known(3): COX-1, which i s constitutively expressed in most tissues, is responsible for the phy siological production of prostaglandins(4); and COX-2, which is induce d by cytokines, mitogens and endotoxins in inflammatory cells(5), is r esponsible for the elevated production of prostaglandins during inflam mation(6,7). The structure of ovine COX-1 complexed with several NSAID s has been determined(8-10). Here we report the structures of unligand ed murine COX-2 and complexes with flurbiprofen, indomethacin and SC-5 58, a selective COX-2 inhibitor, determined at 3.0 to 25 Angstrom reso lution. These structures explain the structural basis for the selectiv e inhibition of COX-2, and demonstrate some of the conformational chan ges associated with time-dependent inhibition.