1EQH

THE 2.7 ANGSTROM MODEL OF OVINE COX-1 COMPLEXED WITH FLURBIPROFEN

Summary for 1EQH

• Entry DOI: 10.2210/pdb1eqh/pdb
• Related: 1EQG
• Descriptor: PROSTAGLANDIN H2 SYNTHASE-1, 2-acetamido-2-deoxy-beta-D-glucopyranose, octyl beta-D-glucopyranoside, ... (6 entities in total)
• Functional Keywords: egf domain, nsaid binding, flurbiprofen, membrane-binding domain, cyclooxygenase, peroxidase, oxidoreductase, dioxygenase
• Biological source: Ovis aries (sheep)
• Total number of polymer chains: 2
• Total formula weight: 138001.32

Authors

Loll, P.J.,Selinsky, B.S.,Gupta, K.,Sharkey, C.T. (deposition date: 2000-04-04, release date: 2001-04-11, Last modification date: 2024-03-13)

Primary citation

Selinsky, B.S.,Gupta, K.,Sharkey, C.T.,Loll, P.J.
Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations.
Biochemistry, 40:5172-5180, 2001

PubMed Abstract: 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.

PubMed: 11318639
DOI: 10.1021/bi010045s

Experimental method

X-RAY DIFFRACTION (2.7 Å)