Motion in aldose reductase [aldr]

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Classification Suspected Domain Motion, Neither Hinge nor Shear Mechanism [D-n-2]

Structures
1ADS Conformation 2 [ PartsList ]
1MAR Conformation 1 [ PartsList ]
2ACQ w/nadp+ and Glc-6-PConformation 3 [ PartsList ]
2ACR w/nadp+ and CacodylatConformation 4 [ PartsList ]
2ACS w/nadp+ and citrateConformation 5 [ PartsList ]

Description
Paraphrasing the abstract to Urzhumtsev et al. (1997): Aldose reductase (AR), an NADPH-dependent enzyme, is 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. An anionic binding site exists near the NADP+. An inhibitor, zopolrestat, binds to this anionic site, and in the hydrophobic cleft, after a change of conformation which opens a specificity pocket. The crystal structures of the porcine AR holoenzyme and its complexes with the inhibitors tolrestat and sorbinil were solved by Urzhumtsev et al. (1997). They analyzed the active site of the holoenzyme, 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 the tolrestat inhibitor includes the specificity pocket. The conformational change leading to the opening of the specificity pocket upon tolrestat inhibitor binding is different to the one seen upon zopolrestat inhibitor binding; this pocket binds inhibitors that are more effective against AR than against aldehyde reductase. From these findings, Urzhumtsev et al. (1997) conclude that the active site of AR adapts itself to bind tightly to different inhibitors; this happens both upon binding to the hydrophilic heads of the inhibitor, and at the hydrophobic and specificity pockets of AR, which, they conclude, can change their shape through different conformational changes of the same residues. They speculate that this flexibility could explain the large variety of possible substrates of AR.

Particular values describing motion
= x (Traditional x-ray)
Creation Date = 19971130
Modification Date = 19971130

References
Urzhumtsev A, Tete-Favier F, Mitschler A, Barbanton J, Barth P, Urzhumtseva L, Biellmann JF, Podjarny A, Moras D (1997). A 'specificity' pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil. Structure 5(5):601-612. [Medline info for 97341224]

GO terms associated with structures
Molecular functionoxidoreductase activity

Morphs

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Best representative
Morph Morph name Structure #1 Structure #2 Residues
Aldose Reductase 1mar [ A ] 2acq [ A ] 315

User-submitted morphs
Morph Morph name Structure #1 Structure #2 Residues
06335-14768 Aldose Reductase 1mar [ A ] 2acr [ A ] 315
06369-14933 Aldose Reductase 1mar [ A ] 2acs [ A ] 315
06467-15248 Aldose Reductase 2acq [ A ] 2acs [ A ] 315
06487-15304 Aldose Reductase 2acr [ A ] 2acs [ A ] 315


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Copyright 1995-2005 M. Gerstein, W. Krebs, S. Flores, N. Echols, and others
Email: Mark.Gerstein _at_ yale.edu