Picturing aspirin's targets.

Researchers have used X-ray crystallography to create for the first time an image of the structure of prostaglandin H synthase-1 (PGHS-1), one of the enzymes that aspirin affects. The finding may help them design an aspirin with fewer side effects, they report in the Jan. 20NATURE.

Scientists had known that aspirin operates by inhibiting the activity of PGHS-1 and PGHS-2, but they understood little about the structures of those enzymes, says coauthor R. Michael Garavito of the University of Chicago. The enzymes help convert fatty acids into prostaglandins, which are involved in inflammation, clotting and other processes. Whereas PGHS-1 acts as a housekeeper, regularly controlling stomach acids, for example, PGHS-2 primarily responds to injuries, Garavito says.

The blue line in this photo sketches a skeleton of atoms in the enzyme. The aspirin lodges itself in the cyclooxygenase active site channel (pink), which lies within that skeleton. The aspirin modifies the amino acid serine 530 (located where the yellow-green line meets the channel, below the heme, in red). Aspirin adds new atoms to serine 530, thereby preventing essential fatty acids from reaching it. This destroys PGHS-1, says Garavito.