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1ebv
From Proteopedia
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[[Image:1ebv.jpg|left|200px]] | [[Image:1ebv.jpg|left|200px]] | ||
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'''OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID''' | '''OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID''' | ||
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[[Category: Loll, P J.]] | [[Category: Loll, P J.]] | ||
[[Category: Sharkey, C T.]] | [[Category: Sharkey, C T.]] | ||
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:55:01 2008'' | |
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Revision as of 11:55, 2 May 2008
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. 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 Fri May 2 14:55:01 2008
