1eqg: Difference between revisions

Revision as of 13:30, 21 February 2008

THE 2.6 ANGSTROM MODEL OF OVINE COX-1 COMPLEXED WITH IBUPROFEN

OverviewOverview

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.

About this StructureAbout this Structure

1EQG is a Single protein structure of sequence from Ovis aries with , , and as ligands. Active as Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 Full crystallographic information is available from OCA.

ReferenceReference

Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations., Selinsky BS, Gupta K, Sharkey CT, Loll PJ, Biochemistry. 2001 May 1;40(17):5172-80. PMID:11318639

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-[[Image:1eqg.gif|left|200px]]<br /><applet load="1eqg" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1eqg.gif|left|200px]]<br /><applet load="1eqg" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1eqg, resolution 2.61&Aring;" />
 '''THE 2.6 ANGSTROM MODEL OF OVINE COX-1 COMPLEXED WITH IBUPROFEN'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-EQG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries] with NAG, BOG, HEM and IBP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EQG OCA].
+EQG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=BOG:'>BOG</scene>, <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=IBP:'>IBP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EQG OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Gupta, K.]]
-[[Category: Loll, P.J.]]
+[[Category: Loll, P J.]]
-[[Category: Selinsky, B.S.]]
+[[Category: Selinsky, B S.]]
-[[Category: Sharkey, C.T.]]
+[[Category: Sharkey, C T.]]
 [[Category: BOG]]
 [[Category: HEM]]
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 [[Category: peroxidase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 14:13:48 2007''
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