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.
MeSH terms
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Acetylation
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Amino Acid Sequence
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Aspirin / analogs & derivatives
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Aspirin / chemistry*
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Aspirin / pharmacology*
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Binding Sites
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Crystallography, X-Ray
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Cyclooxygenase Inhibitors / chemistry*
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Cyclooxygenase Inhibitors / pharmacology*
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Kinetics
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Models, Molecular
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Molecular Conformation
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Prostaglandin-Endoperoxide Synthases / chemistry*
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Protein Conformation*
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Protein Structure, Secondary
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Serine
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Sheep
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase Inhibitors
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Isoenzymes
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Serine
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bromoaspirin
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Prostaglandin-Endoperoxide Synthases
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Aspirin