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PDBsum entry 1eqh
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Oxidoreductase
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PDB id
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1eqh
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural analysis of nsaid binding by prostaglandin h2 synthase: time-Dependent and time-Independent inhibitors elicit identical enzyme conformations.
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Authors
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B.S.Selinsky,
K.Gupta,
C.T.Sharkey,
P.J.Loll.
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Ref.
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Biochemistry, 2001,
40,
5172-5180.
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PubMed id
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Abstract
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Nonsteroidal antiinflammatory drugs (NSAIDs) block prostanoid biosynthesis by
inhibiting prostaglandin H(2) synthase (EC 1.14.99.1). NSAIDs are either rapidly
reversible competitive inhibitors or slow tight-binding inhibitors of this
enzyme. These different modes of inhibition correlate with clinically important
differences in isoform selectivity. Hypotheses have been advanced to explain the
different inhibition kinetics, but no structural data have been available to
test them. We present here crystal structures of prostaglandin H(2) synthase-1
in complex with the inhibitors ibuprofen, methyl flurbiprofen, flurbiprofen, and
alclofenac at resolutions ranging from 2.6 to 2.75 A. These structures allow
direct comparison of enzyme complexes with reversible competitive inhibitors
(ibuprofen and methyl flurbiprofen) and slow tight-binding inhibitors
(alclofenac and flurbiprofen). The four inhibitors bind to the same site and
adopt similar conformations. In all four complexes, the enzyme structure is
essentially unchanged, exhibiting only minimal differences in the inhibitor
binding site. These results argue strongly against hypotheses that explain the
difference between slow tight-binding and fast reversible competitive inhibition
by invoking global conformational differences or different inhibitor binding
sites. Instead, they suggest that the different apparent modes of NSAID binding
may result from differences in the speed and efficiency with which inhibitors
can perturb the hydrogen bonding network around Arg-120 and Tyr-355.
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