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

Nature Structural Biology volume 2, pages 637–643 (1995)Cite this article

Abstract

Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS). Here we present the 3.4 Å 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.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Chicago, 920 E. 58th Street, Chicago, Illinois, 60637, USA

    Patrick J. Loll & R. Michael Garavito

  2. Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 5005, Paris, France

    Daniel Picot

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Loll, P., Picot, D. & Garavito, R. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Mol Biol 2, 637–643 (1995). https://doi.org/10.1038/nsb0895-637

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