1ah4: Difference between revisions

Revision as of 12:44, 21 February 2008

PIG ALDOSE REDUCTASE, HOLO FORM

OverviewOverview

BACKGROUND: Aldose reductase (AR) is an NADPH-dependent enzyme implicated in long-term diabetic complications. Buried at the bottom of a deep hydrophobic cleft, the NADPH coenzyme is surrounded by the conserved hydrophilic residues of the AR active site. The existence of an anionic binding site near the NADP+ has been determined from the structures of the complexes of AR with citrate, cacodylate and glucose-6-phosphate. The inhibitor zopolrestat binds to this anionic site, and in the hydrophobic cleft, after a change of conformation which opens a 'specificity' pocket. RESULTS: The crystal structures of the porcine AR holoenzyme and its complexes with the inhibitors tolrestat and sorbinil have been solved; these structures are important as tolrestat and sorbinil are, pharmaceutically, the most well-studied AR inhibitors. The active site of the holoenzyme was analyzed, and binding of the inhibitors was found to involve two contact zones in the active site: first, a recognition region for hydrogen-bond acceptors near the coenzyme, with three centers, including the anionic site; and second, a hydrophobic contact zone in the active-site cleft, which in the case of tolrestat includes the specificity pocket. The conformational change leading to the opening of the specificity pocket upon tolrestat binding is different to the one seen upon zopolrestat binding; this pocket binds inhibitors that are more effective against AR than against aldehyde reductase. CONCLUSIONS: The active site of AR adapts itself to bind tightly to different inhibitors; this happens both upon binding to the inhibitor's hydrophilic heads, and at the hydrophobic and specificity pockets of AR, which can change their shape through different conformational changes of the same residues. This flexibility could explain the large variety of possible substrates of AR.

About this StructureAbout this Structure

1AH4 is a Single protein structure of sequence from Sus scrofa with as ligand. Active as Aldehyde reductase, with EC number 1.1.1.21 Full crystallographic information is available from OCA.

ReferenceReference

A 'specificity' pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil., Urzhumtsev A, Tete-Favier F, Mitschler A, Barbanton J, Barth P, Urzhumtseva L, Biellmann JF, Podjarny A, Moras D, Structure. 1997 May 15;5(5):601-12. PMID:9195881

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-[[Image:1ah4.gif|left|200px]]<br /><applet load="1ah4" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="1ah4, resolution 2.0&Aring;" />
 '''PIG ALDOSE REDUCTASE, HOLO FORM'''<br />
 ==Overview==
-BACKGROUND: Aldose reductase (AR) is an NADPH-dependent enzyme implicated, in long-term diabetic complications. Buried at the bottom of a deep, hydrophobic cleft, the NADPH coenzyme is surrounded by the conserved, hydrophilic residues of the AR active site. The existence of an anionic, binding site near the NADP+ has been determined from the structures of the, complexes of AR with citrate, cacodylate and glucose-6-phosphate. The, inhibitor zopolrestat binds to this anionic site, and in the hydrophobic, cleft, after a change of conformation which opens a 'specificity' pocket., RESULTS: The crystal structures of the porcine AR holoenzyme and its, complexes with the inhibitors tolrestat and sorbinil have been solved;, these structures are important as tolrestat and sorbinil are, pharmaceutically, the most well-studied AR inhibitors. The active site of, the holoenzyme was analyzed, and binding of the inhibitors was found to, involve two contact zones in the active site: first, a recognition region, for hydrogen-bond acceptors near the coenzyme, with three centers, including the anionic site; and second, a hydrophobic contact zone in the, active-site cleft, which in the case of tolrestat includes the specificity, pocket. The conformational change leading to the opening of the, specificity pocket upon tolrestat binding is different to the one seen, upon zopolrestat binding; this pocket binds inhibitors that are more, effective against AR than against aldehyde reductase. CONCLUSIONS: The, active site of AR adapts itself to bind tightly to different inhibitors;, this happens both upon binding to the inhibitor's hydrophilic heads, and, at the hydrophobic and specificity pockets of AR, which can change their, shape through different conformational changes of the same residues. This, flexibility could explain the large variety of possible substrates of AR.
+BACKGROUND: Aldose reductase (AR) is an NADPH-dependent enzyme implicated in long-term diabetic complications. Buried at the bottom of a deep hydrophobic cleft, the NADPH coenzyme is surrounded by the conserved hydrophilic residues of the AR active site. The existence of an anionic binding site near the NADP+ has been determined from the structures of the complexes of AR with citrate, cacodylate and glucose-6-phosphate. The inhibitor zopolrestat binds to this anionic site, and in the hydrophobic cleft, after a change of conformation which opens a 'specificity' pocket. RESULTS: The crystal structures of the porcine AR holoenzyme and its complexes with the inhibitors tolrestat and sorbinil have been solved; these structures are important as tolrestat and sorbinil are, pharmaceutically, the most well-studied AR inhibitors. The active site of the holoenzyme was analyzed, and binding of the inhibitors was found to involve two contact zones in the active site: first, a recognition region for hydrogen-bond acceptors near the coenzyme, with three centers, including the anionic site; and second, a hydrophobic contact zone in the active-site cleft, which in the case of tolrestat includes the specificity pocket. The conformational change leading to the opening of the specificity pocket upon tolrestat binding is different to the one seen upon zopolrestat binding; this pocket binds inhibitors that are more effective against AR than against aldehyde reductase. CONCLUSIONS: The active site of AR adapts itself to bind tightly to different inhibitors; this happens both upon binding to the inhibitor's hydrophilic heads, and at the hydrophobic and specificity pockets of AR, which can change their shape through different conformational changes of the same residues. This flexibility could explain the large variety of possible substrates of AR.
 ==About this Structure==
-AH4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with NAP as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1AH4 OCA].
+AH4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=NAP:'>NAP</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AH4 OCA].
 ==Reference==
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 [[Category: oxidoreductase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 10:50:42 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:44:35 2008''