Arthritis is a debilitating disease that affects over 200 million people world wide. There are ∼100 different forms of arthritis, including osteoarthritis and rheumatoid arthritis. The severe pain and swelling in the joints experienced by patients with this disease result from the inflammation of tissues such as tendons or ligaments. The inflammation response is mediated by prostaglandins, metabolites of arachidonic acid (AA) — a polyunsaturated fatty acid that is an integral component of phospholipid membranes. Cyclooxygenases (COX) catalyze the first step of prostaglandin production from AA; they are pharmacological targets of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. By inhibiting the production of prostaglandins, NSAIDs relieve the symptoms of inflammation.
Prostaglandins also have other physiological roles. For example, they are involved in preventing damage, such as ulcers, to the gastrointestinal tract. Thus, the mechanisms of both the production of prostaglandins and the inhibition of COX are of medical interest. The crystal structures of COX in complex with several NSAIDs and other inhibitors have greatly enhanced our knowledge of how NSAIDs inhibit cyclooxygenases. A similar level of understanding of the COX catalytic mechanism requires the high resolution structure of a COX–AA complex. In a recent issue of Nature (405, 97–101), Keifer et al. reported the crystal structures of the COX-2 isoform in complex with arachidonic acid and prostaglandin.
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