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Title
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The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.
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Authors
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P.J.Loll,
D.Picot,
R.M.Garavito.
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Ref.
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Nat Struct Biol, 1995,
2,
637-643.
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PubMed id
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Abstract
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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.
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