1ebv
From Proteopedia
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OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID
Overview
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.
About this Structure
1EBV is a Single protein structure of sequence from Ovis aries with NAG, SCL and HEM as ligands. Active as Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 Full crystallographic information is available from OCA.
Reference
O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions., Loll PJ, Sharkey CT, O'Connor SJ, Dooley CM, O'Brien E, Devocelle M, Nolan KB, Selinsky BS, Fitzgerald DJ, Mol Pharmacol. 2001 Dec;60(6):1407-13. PMID:11723249
Page seeded by OCA on Tue Nov 20 13:53:00 2007
