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
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