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Nat Struct Biol. 1995 Aug;2(8):637-43.

The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.

Author information

  • 1Department of Biochemistry and Molecular Biology, University of Chicago, Illinois 60637, USA.

Abstract

Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS). Here we present the 3.4 A resolution X-ray crystal structure of PGHS isoform-1 inactivated by the potent aspirin analogue 2-bromoacetoxy-benzoic acid. Acetylation by this analogue abolishes cyclooxygenase activity by steric blockage of the active-site channel and not through a large conformational change. We observe two rotameric states of the acetyl-serine side chain which block the channel to different extents, a result which may explain the dissimilar effects of aspirin on the two PGHS isoforms. We also observe the product salicylic acid binding at a site consistent with its antagonistic effect on aspirin activity.

Comment in

  • Aspirin and inflammation. [Nat Struct Biol. 1995]
PMID:
7552725
[PubMed - indexed for MEDLINE]
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