1EBV

OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID

Summary for 1EBV

• Entry DOI: 10.2210/pdb1ebv/pdb
• Descriptor: PROSTAGLANDIN H2 SYNTHASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: monotopic membrane protein, oxidoreductase
• Biological source: Ovis aries (sheep)
• Total number of polymer chains: 1
• Total formula weight: 65232.45

Authors

Loll, P.J.,Sharkey, C.T.,O'Connor, S.J.,Fitzgerald, D.J. (deposition date: 2000-01-24, release date: 2000-02-24, Last modification date: 2024-10-16)

Primary citation

Loll, P.J.,Sharkey, C.T.,O'Connor, S.J.,Dooley, C.M.,O'Brien, E.,Devocelle, M.,Nolan, K.B.,Selinsky, B.S.,Fitzgerald, D.J.
O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions.
Mol.Pharmacol., 60:1407-1413, 2001

PubMed Abstract: 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.

PubMed: 11723249

Experimental method

X-RAY DIFFRACTION (3.2 Å)