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PDBsum entry 2pdp
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Oxidoreductase
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PDB id
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2pdp
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References listed in PDB file
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Key reference
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Title
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Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-Determining features.
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Authors
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H.Steuber,
A.Heine,
A.Podjarny,
G.Klebe.
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Ref.
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J Mol Biol, 2008,
379,
991-1016.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic
concept to prevent late complications of diabetes. As well as appropriate
affinity and bioavailability, putative inhibitors should possess a high level of
selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated
the selectivity-determining features by gradually mapping the residues deviating
between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The
resulting mutational constructs of ALR2 (eight point mutations and one double
mutant) were probed for their influence towards ligand selectivity by X-ray
structure analysis of the corresponding complexes and isothermal titration
calorimetry (ITC). The binding properties of these mutants were evaluated using
a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393,
sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations
within the mutated binding site as an essential prerequisite for ligand
accommodation related to the selectivity discrimination of the ligands. However,
our study also highlights the limits of the present understanding of
protein-ligand interactions. Interestingly, binding site mutations not involved
in any direct interaction to the ligands in various cases show significant
effects towards their binding thermodynamics. Furthermore, our results suggest
the binding site residues deviating between ALR1 and ALR2 influence ligand
affinity in a complex interplay, presumably involving changes of dynamic
properties and differences of the solvation/desolvation balance upon ligand
binding.
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Figure 1.
Fig. 1. Comparative stereo representations of the related
ALR1 (a) and ALR2 (b) inhibitor binding pockets.
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Figure 2.
Fig. 2. Chemical formulae of the ALR2 inhibitors investigated
in this study.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
379,
991-1016)
copyright 2008.
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