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PDBsum entry 1mar
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Oxidoreductase(NADP) PDB id
1mar
Contents
Protein chain
315 a.a.* *
Ligands
NAP
ZST
* Residue conservation analysis
* C-alpha coords only
PDB id:
1mar
Name: Oxidoreductase(NADP)
Title: Refined 1.8 angstroms structure of human aldose reductase complexed with the potent inhibitor zopolrestat
Structure: Aldose reductase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.80Å     R-factor:   0.180    
Authors: D.K.Wilson,F.A.Quiocho
Key ref: D.K.Wilson et al. (1993). Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat. Proc Natl Acad Sci U S A, 90, 9847-9851. PubMed id: 8234324 DOI: 10.1073/pnas.90.21.9847
Date:
20-Jul-93     Release date:   20-Jul-95    
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P15121  (ALDR_HUMAN) -  Aldo-keto reductase family 1 member B1 from Homo sapiens
Seq:
Struc: 		316 a.a.
315 a.a.
Key:    PfamA domain  Secondary structure

 Enzyme reactions 
   Enzyme class 1: E.C.1.1.1.21  - aldose reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. an alditol + NAD+ = an aldose + NADH + H+
2. an alditol + NADP+ = an aldose + NADPH + H+
alditol
 +
NAD(+)
Bound ligand (Het Group name = NAP)
matches with 91.67% similarity 		= aldose
 + NADH
 + H(+)
alditol
 +
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= aldose
 + NADPH
 + H(+)
   Enzyme class 2: E.C.1.1.1.300  - NADP-retinol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: all-trans-retinol + NADP+ = all-trans-retinal + NADPH + H+
all-trans-retinol
 +
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= all-trans-retinal
 + NADPH
 + H(+)
   Enzyme class 3: E.C.1.1.1.372  - D/L-glyceraldehyde reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. glycerol + NADP+ = L-glyceraldehyde + NADPH + H+
2. glycerol + NADP+ = D-glyceraldehyde + NADPH + H+
glycerol
 +
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= L-glyceraldehyde
 + NADPH
 + H(+)
glycerol
 +
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= D-glyceraldehyde
 + NADPH
 + H(+)
   Enzyme class 4: E.C.1.1.1.54  - allyl-alcohol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: allyl alcohol + NADP+ = acrolein + NADPH + H+
allyl alcohol
 +
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= acrolein
 + NADPH
 + H(+)
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1073/pnas.90.21.9847 Proc Natl Acad Sci U S A 90:9847-9851 (1993)
PubMed id: 8234324  
 
 
Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.
D.K.Wilson, I.Tarle, J.M.Petrash, F.A.Quiocho.
 
  ABSTRACT  
 
As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket. Excellent complementarity and affinity are achieved on inhibitor binding by the formation of 110 contacts (< or = 4 A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9 with four water molecules. The structure is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20848551 A.Ahmed, S.Villinger, and H.Gohlke (2010).
Large-scale comparison of protein essential dynamics from molecular dynamics simulations and coarse-grained normal mode analyses.
  Proteins, 78, 3341-3352.  
18949601 O.A.Barski, S.M.Tipparaju, and A.Bhatnagar (2008).
The aldo-keto reductase superfamily and its role in drug metabolism and detoxification.
  Drug Metab Rev, 40, 553-624.  
17654552 V.Carbone, S.Endo, R.Sumii, R.P.Chung, T.Matsunaga, A.Hara, and O.El-Kabbani (2008).
Structures of dimeric dihydrodiol dehydrogenase apoenzyme and inhibitor complex: probing the subunit interface with site-directed mutagenesis.
  Proteins, 70, 176-187.
PDB codes: 2o48 2o4u
17351966 D.Rakowitz, G.Piccolruaz, C.Pirker, and B.Matuszczak (2007).
Novel aldose reductase inhibitors derived from 6-[[(diphenylmethylene)amino]oxy]hexanoic acid.
  Arch Pharm (Weinheim), 340, 202-208.  
17202704 L.K.Soni, and S.G.Kaskhedikar (2007).
Exploring structural feature of aldose-reductase inhibition by 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives employing Fujita-Ban and Hansch approach.
  Chem Pharm Bull (Tokyo), 55, 72-75.  
17505104 M.Biadene, I.Hazemann, A.Cousido, S.Ginell, A.Joachimiak, G.M.Sheldrick, A.Podjarny, and T.R.Schneider (2007).
The atomic resolution structure of human aldose reductase reveals that rearrangement of a bound ligand allows the opening of the safety-belt loop.
  Acta Crystallogr D Biol Crystallogr, 63, 665-672.
PDB code: 2j8t
17009300 D.Rakowitz, A.Gmeiner, and B.Matuszczak (2006).
Discovery of novel aldose reductase inhibitors characterized by an alkoxy-substituted phenylacetic acid core.
  Arch Pharm (Weinheim), 339, 559-563.  
17009299 D.Rakowitz, H.Angerer, and B.Matuszczak (2006).
Synthesis and aldose reductase inhibitory activities of novel O-substituted hydroxyphenylacetic acid derivatives.
  Arch Pharm (Weinheim), 339, 547-558.  
17083960 J.M.Brownlee, E.Carlson, A.C.Milne, E.Pape, and D.H.Harrison (2006).
Structural and thermodynamic studies of simple aldose reductase-inhibitor complexes.
  Bioorg Chem, 34, 424-444.
PDB codes: 2ine 2inz 2ipw 2iq0 2iqd 2is7 2isf
16639747 R.Singh, M.A.White, K.V.Ramana, J.M.Petrash, S.J.Watowich, A.Bhatnagar, and S.K.Srivastava (2006).
Structure of a glutathione conjugate bound to the active site of aldose reductase.
  Proteins, 64, 101-110.
PDB code: 2f2k
16143954 D.Rakowitz, B.Hennig, M.Nagano, S.Steger, L.Costantino, and B.Matuszczak (2005).
Synthesis of novel benzoic acid derivatives with benzothiazolyl subunit and evaluation as aldose reductase inhibitors.
  Arch Pharm (Weinheim), 338, 411-418.  
16143958 D.Rakowitz, P.Muigg, N.Schröder, and B.Matuszczak (2005).
On the synthesis of bioisosters of o-benzothiazolyloxybenzoic acids and evaluation as aldose reductase inhibitors.
  Arch Pharm (Weinheim), 338, 419-426.  
15146478 E.I.Howard, R.Sanishvili, R.E.Cachau, A.Mitschler, B.Chevrier, P.Barth, V.Lamour, M.Van Zandt, E.Sibley, C.Bon, D.Moras, T.R.Schneider, A.Joachimiak, and A.Podjarny (2004).
Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.
  Proteins, 55, 792-804.
PDB code: 1us0
15272156 F.Ruiz, I.Hazemann, A.Mitschler, A.Joachimiak, T.Schneider, M.Karplus, and A.Podjarny (2004).
The crystallographic structure of the aldose reductase-IDD552 complex shows direct proton donation from tyrosine 48.
  Acta Crystallogr D Biol Crystallogr, 60, 1347-1354.
PDB codes: 1t40 1t41
15146479 O.El-Kabbani, C.Darmanin, T.R.Schneider, I.Hazemann, F.Ruiz, M.Oka, A.Joachimiak, C.Schulze-Briese, T.Tomizaki, A.Mitschler, and A.Podjarny (2004).
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.
  Proteins, 55, 805-813.
PDB codes: 1pwl 1pwm
15146480 O.Kraemer, I.Hazemann, A.D.Podjarny, and G.Klebe (2004).
Virtual screening for inhibitors of human aldose reductase.
  Proteins, 55, 814-823.  
14517983 G.Obmolova, A.Teplyakov, P.P.Khil, A.J.Howard, R.D.Camerini-Otero, and G.L.Gilliland (2003).
Crystal structure of the Escherichia coli Tas protein, an NADP(H)-dependent aldo-keto reductase.
  Proteins, 53, 323-325.
PDB code: 1lqa
12935348 M.L.Teodoro, G.N.Phillips, and L.E.Kavraki (2003).
Understanding protein flexibility through dimensionality reduction.
  J Comput Biol, 10, 617-634.  
12486717 O.El-Kabbani, P.Ramsland, C.Darmanin, R.P.Chung, and A.Podjarny (2003).
Structure of human aldose reductase holoenzyme in complex with statil: an approach to structure-based inhibitor design of the enzyme.
  Proteins, 50, 230-238.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
  12897449 U.Mura, M.Cappiello, P.G.Vilardo, I.Cecconi, M.Dal Monte, and A.Del Corso (2003).
Signalling potential and protein modifying ability of physiological thiols.
  Biofactors, 17, 279-285.  
11914486 T.Kinoshita, H.Miyake, T.Fujii, S.Takakura, and T.Goto (2002).
The structure of human recombinant aldose reductase complexed with the potent inhibitor zenarestat.
  Acta Crystallogr D Biol Crystallogr, 58, 622-626.
PDB code: 1iei
11358692 A.C.Anderson, R.H.O'Neil, T.S.Surti, and R.M.Stroud (2001).
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
  Chem Biol, 8, 445-457.
PDB code: 1f28
11306077 B.Nidetzky, P.Mayr, W.Neuhauser, and M.Puchberger (2001).
Structural and functional properties of aldose xylose reductase from the D-xylose-metabolizing yeast Candida tenuis.
  Chem Biol Interact, 130, 583-595.  
10818358 E.Hur, and D.K.Wilson (2000).
Crystallization and aldo-keto reductase activity of Gcy1p from Saccharomyces cerevisiae.
  Acta Crystallogr D Biol Crystallogr, 56, 763-765.  
10882025 G.Rastelli, L.Antolini, S.Benvenuti, and L.Costantino (2000).
Structural bases for the inhibition of aldose reductase by phenolic compounds.
  Bioorg Med Chem, 8, 1151-1158.  
10933817 K.M.Bohren, and C.E.Grimshaw (2000).
The sorbinil trap: a predicted dead-end complex confirms the mechanism of aldose reductase inhibition.
  Biochemistry, 39, 9967-9974.  
10644040 K.Sugiyama, Z.Chen, Y.S.Lee, and P.F.Kador (2000).
Isolation of a non-covalent aldose reductase-nucleotide-inhibitor complex.
  Biochem Pharmacol, 59, 329-336.  
11015195 K.V.Ramana, B.L.Dixit, S.Srivastava, G.K.Balendiran, S.K.Srivastava, and A.Bhatnagar (2000).
Selective recognition of glutathiolated aldehydes by aldose reductase.
  Biochemistry, 39, 12172-12180.  
11025551 O.El-Kabbani, H.Rogniaux, P.Barth, R.P.Chung, E.V.Fletcher, A.Van Dorsselaer, and A.Podjarny (2000).
Aldose and aldehyde reductases: correlation of molecular modeling and mass spectrometric studies on the binding of inhibitors to the active site.
  Proteins, 41, 407-414.  
10651037 Q.Ye, D.Hyndman, X.Li, T.G.Flynn, and Z.Jia (2000).
Crystal structure of CHO reductase, a member of the aldo-keto reductase superfamily.
  Proteins, 38, 41-48.
PDB code: 1c9w
10771421 V.Calderone, B.Chevrier, M.Van Zandt, V.Lamour, E.Howard, A.Poterszman, P.Barth, A.Mitschler, J.Lu, D.M.Dvornik, G.Klebe, O.Kraemer, A.R.Moorman, D.Moras, and A.Podjarny (2000).
The structure of human aldose reductase bound to the inhibitor IDD384.
  Acta Crystallogr D Biol Crystallogr, 56, 536-540.
PDB codes: 1eko 1el3
10384727 H.Rogniaux, A.Van Dorsselaer, P.Barth, J.F.Biellmann, J.Barbanton, M.van Zandt, B.Chevrier, E.Howard, A.Mitschler, N.Potier, L.Urzhumtseva, D.Moras, and A.Podjarny (1999).
Binding of aldose reductase inhibitors: correlation of crystallographic and mass spectrometric studies.
  J Am Soc Mass Spectrom, 10, 635-647.  
9918192 L.Costantino, G.Rastelli, P.Vianello, G.Cignarella, and D.Barlocco (1999).
Diabetes complications and their potential prevention: aldose reductase inhibition and other approaches.
  Med Res Rev, 19, 3.  
11139842 P.J.Oates, and B.L.Mylari (1999).
Aldose reductase inhibitors: therapeutic implications for diabetic complications.
  Expert Opin Investig Drugs, 8, 2095-2119.  
9890881 S.Srivastava, S.J.Watowich, J.M.Petrash, S.K.Srivastava, and A.Bhatnagar (1999).
Structural and kinetic determinants of aldehyde reduction by aldose reductase.
  Biochemistry, 38, 42-54.  
9695797 M.J.Crabbe, and D.Goode (1998).
Aldose reductase: a window to the treatment of diabetic complications?
  Prog Retin Eye Res, 17, 313-383.  
9665698 M.Nakasako, T.Motoyama, Y.Kurahashi, and I.Yamaguchi (1998).
Cryogenic X-ray crystal structure analysis for the complex of scytalone dehydratase of a rice blast fungus and its tight-binding inhibitor, carpropamid: the structural basis of tight-binding inhibition.
  Biochemistry, 37, 9931-9939.
PDB code: 2std
9737870 S.Srivastava, T.M.Harter, A.Chandra, A.Bhatnagar, S.K.Srivastava, and J.M.Petrash (1998).
Kinetic studies of FR-1, a growth factor-inducible aldo-keto reductase.
  Biochemistry, 37, 12909-12917.  
9546197 Y.S.Lee, M.Hodoscek, B.R.Brooks, and P.F.Kador (1998).
Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics.
  Biophys Chem, 70, 203-216.  
9537432 Z.Scuric, S.C.Stain, W.F.Anderson, and J.J.Hwang (1998).
New member of aldose reductase family proteins overexpressed in human hepatocellular carcinoma.
  Hepatology, 27, 943-950.  
9195881 A.Urzhumtsev, F.Tête-Favier, A.Mitschler, J.Barbanton, P.Barth, L.Urzhumtseva, J.F.Biellmann, A.Podjarny, and D.Moras (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, 601-612.
PDB codes: 1ah0 1ah3 1ah4
9261071 M.J.Bennett, R.H.Albert, J.M.Jez, H.Ma, T.M.Penning, and M.Lewis (1997).
Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase.
  Structure, 5, 799-812.
PDB code: 1afs
9030749 N.Potier, P.Barth, D.Tritsch, J.F.Biellmann, and A.Van Dorsselaer (1997).
Study of non-covalent enzyme-inhibitor complexes of aldose reductase by electrospray mass spectrometry.
  Eur J Biochem, 243, 274-282.  
9329083 O.el-Kabbani, D.A.Carper, M.H.McGowan, Y.Devedjiev, K.J.Rees-Milton, and T.G.Flynn (1997).
Studies on the inhibitor-binding site of porcine aldehyde reductase: crystal structure of the holoenzyme-inhibitor ternary complex.
  Proteins, 29, 186-192.
PDB code: 1ae4
8718859 M.J.Bennett, B.P.Schlegel, J.M.Jez, T.M.Penning, and M.Lewis (1996).
Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+.
  Biochemistry, 35, 10702-10711.
PDB code: 1lwi
8916913 O.A.Barski, K.H.Gabbay, and K.M.Bohren (1996).
The C-terminal loop of aldehyde reductase determines the substrate and inhibitor specificity.
  Biochemistry, 35, 14276-14280.  
8780524 T.Nakano, and J.M.Petrash (1996).
Kinetic and spectroscopic evidence for active site inhibition of human aldose reductase.
  Biochemistry, 35, 11196-11202.  
7552731 O.el-Kabbani, K.Judge, S.L.Ginell, D.A.Myles, L.J.DeLucas, and T.G.Flynn (1995).
Structure of porcine aldehyde reductase holoenzyme.
  Nat Struct Biol, 2, 687-692.  
7851421 T.Gui, T.Tanimoto, Y.Kokai, and C.Nishimura (1995).
Presence of a closely related subgroup in the aldo-ketoreductase family of the mouse.
  Eur J Biochem, 227, 448-453.  
7714750 V.J.Demopoulos, and E.Rekka (1995).
Isomeric benzoylpyrroleacetic acids: some structural aspects for aldose reductase inhibitory and anti-inflammatory activities.
  J Pharm Sci, 84, 79-82.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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