The productive conformation of arachidonic acid bound to prostaglandin synthase.
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.
Malkowski
M G
MG
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319, USA.
Ginell
S L
SL
Smith
W L
WL
Garavito
R M
RM
D016718:Arachidonic Acid / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation
D007527:Isoenzymes; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases