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PDBsum entry 1pwm
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Oxidoreductase
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PDB id
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1pwm
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Ultrahigh resolution drug design. Ii. Atomic resolution structures of human aldose reductase holoenzyme complexed with fidarestat and minalrestat: implications for the binding of cyclic imide inhibitors.
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Authors
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O.El-Kabbani,
C.Darmanin,
T.R.Schneider,
I.Hazemann,
F.Ruiz,
M.Oka,
A.Joachimiak,
C.Schulze-Briese,
T.Tomizaki,
A.Mitschler,
A.Podjarny.
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Ref.
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Proteins, 2004,
55,
805-813.
[DOI no: ]
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PubMed id
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Abstract
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The X-ray structures of human aldose reductase holoenzyme in complex with the
inhibitors Fidarestat (SNK-860) and Minalrestat (WAY-509) were determined at
atomic resolutions of 0.92 A and 1.1 A, respectively. The hydantoin and
succinimide moieties of the inhibitors interacted with the conserved
anion-binding site located between the nicotinamide ring of the coenzyme and
active site residues Tyr48, His110, and Trp111. Minalrestat's hydrophobic
isoquinoline ring was bound in an adjacent pocket lined by residues Trp20,
Phe122, and Trp219, with the bromo-fluorobenzyl group inside the
"specificity" pocket. The interactions between Minalrestat's
bromo-fluorobenzyl group and the enzyme include the stacking against the
side-chain of Trp111 as well as hydrogen bonding distances with residues Leu300
and Thr113. The carbamoyl group in Fidarestat formed a hydrogen bond with the
main-chain nitrogen atom of Leu300. The atomic resolution refinement allowed the
positioning of hydrogen atoms and accurate determination of bond lengths of the
inhibitors, coenzyme NADP+ and active-site residue His110. The 1'-position
nitrogen atom in the hydantoin and succinimide moieties of Fidarestat and
Minalrestat, respectively, form a hydrogen bond with the Nepsilon2 atom of His
110. For Fidarestat, the electron density indicated two possible positions for
the H-atom in this bond. Furthermore, both native and anomalous difference maps
indicated the replacement of a water molecule linked to His110 by a Cl-ion.
These observations suggest a mechanism in which Fidarestat is bound protonated
and becomes negatively charged by donating the proton to His110, which may have
important implications on drug design.
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Figure 5.
Figure 5. Stereoviews of (a) Fidarestat and (b) Minalrestat
bound into the active site of the human ALR2 holoenzyme.
Residues within 4 Å of the compounds with hydrogen bonds
(yellow solid lines) and close contacts (green solid lines) are
shown.
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Figure 6.
Figure 6. Proposed mechanism of binding of Fidarestat (SNK-860).
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2004,
55,
805-813)
copyright 2004.
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