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Science 15 September 2000:
Vol. 289. no. 5486, pp. 1933 - 1937
DOI: 10.1126/science.289.5486.1933
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Reports

The Productive Conformation of Arachidonic Acid Bound to Prostaglandin Synthase

M. G. Malkowski,1 S. L. Ginell,2 W. L. Smith,1 R. M. Garavito1*

Prostaglandin H synthase-1 and -2 (PGHS-1 and -2) catalyze the committed step in prostaglandin synthesis and are targets for nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin. We have determined the structure of PGHS-1 at 3 angstrom resolution with arachidonic acid (AA) bound in a chemically productive conformation. The fatty acid adopts an extended L-shaped conformation that positions the 13proS hydrogen of AA for abstraction by tyrosine-385, the likely radical donor. A space also exists for oxygen addition on the antarafacial surface of the carbon in the 11-position (C-11). While this conformation allows endoperoxide formation between C-11 and C-9, it also implies that a subsequent conformational rearrangement must occur to allow formation of the C-8/C-12 bond and to position C-15 for attack by a second molecule of oxygen.

1 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA.
2 Structural Biology Center, Argonne National Laboratory, Argonne, IL 60439, USA.
*   To whom correspondence should be addressed. E-mail: garavito{at}magaera.bch.msu.edu

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