1EQH: The 2.7 Angstrom Model of Ovine Cox-1 Complexed With Flurbiprofen

Citation:
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.
PDB ID: 1EQHDownload
MMDB ID: 16073
PDB Deposition Date: 2000/4/4
Updated in MMDB: 2007/10 
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Similar Structures:
Biological Unit for 1EQH: dimeric; determined by author and by software (PISA)
Molecular Components in 1EQH
Label Count Molecule
Proteins (2 molecules)
2
Prostaglandin H2 Synthase-1(Gene symbol: PTGS1)
Molecule annotation
Chemicals (17 molecules)
1
10
2
3
3
2
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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