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.