Journal
BIOCHEMISTRY
Volume 40, Issue 17, Pages 5172-5180Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi010045s
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- NIGMS NIH HHS [GM55171] Funding Source: Medline
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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 postaglandin H-2 synthase-1 in complex with the inhibitors ibuprofen? methyl flurbiprofen, flurbiprofen, and alclofenac at resolutions ranging from 2.6 to 2.75 Angstrom. These structures allow direct comparison of enzyme complexes with reversible competitive inhibitors (ibuprofen anal 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, exibiting 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 ill the speed and efficiency with which inhibitors can perturb the hydrogen bonding network around Arg-120 and Tyr-355.
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