PDBsum entry 1ebv

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Oxidoreductase PDB id
Protein chain
551 a.a. *
NAG ×2
* Residue conservation analysis

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Key reference
Title O-Acetylsalicylhydroxamic acid, A novel acetylating inhibitor of prostaglandin h2 synthase: structural and functional characterization of enzyme-Inhibitor interactions.
Authors P.J.Loll, C.T.Sharkey, S.J.O'Connor, C.M.Dooley, E.O'Brien, M.Devocelle, K.B.Nolan, B.S.Selinsky, D.J.Fitzgerald.
Ref. Mol Pharmacol, 2001, 60, 1407-1413.
PubMed id 11723249
Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors.
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