PDBsum entry 1ah4

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Oxidoreductase PDB id
Protein chain
315 a.a. *
Waters ×277
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Pig aldose reductase, holo form
Structure: Aldose reductase. Chain: a. Ec:
Source: Sus scrofa. Pig. Organism_taxid: 9823. Organ: eye. Tissue: lens
2.00Å     R-factor:   0.201     R-free:   0.285
Authors: D.Moras,A.Podjarny
Key ref:
A.Urzhumtsev et al. (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. PubMed id: 9195881 DOI: 10.1016/S0969-2126(97)00216-5
12-Apr-97     Release date:   15-Apr-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P80276  (ALDR_PIG) -  Aldose reductase
316 a.a.
315 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   3 terms 
  Biological process     daunorubicin metabolic process   3 terms 
  Biochemical function     oxidoreductase activity     3 terms  


DOI no: 10.1016/S0969-2126(97)00216-5 Structure 5:601-612 (1997)
PubMed id: 9195881  
A 'specificity' pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil.
A.Urzhumtsev, F.Tête-Favier, A.Mitschler, J.Barbanton, P.Barth, L.Urzhumtseva, J.F.Biellmann, A.Podjarny, D.Moras.
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.
  Selected figure(s)  
Figure 1.
Figure 1. Overall views of the holoenzyme form of pig lens AR. (a) Schematic drawing obtained using the program SETOR [37], showing the TIM barrel structure (green), the sorbinil molecule (brown ball-and-stick) and the NADP+ (dark blue ball-and-stick) lying between strands S7 and S8, with loop L7 in light blue bent over it. (b) View of the surface of the molecule generated using the program GRASP [38], with the sorbinil molecule (ball-and-stick) bound in the active-site cleft. The colors correspond to electrostatic potential surfaces (positive in blue; negative in red) calculated using charge distributions on all protein residues using the program XPLOR [32], and on NADP+, from Pavelites et al. [39]. Note the positively charged bottom of the pocket, below the sorbinil molecule.
  The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 601-612) copyright 1997.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19275144 C.Mulakala, and Y.N.Kaznessis (2009).
Path-integral method for predicting relative binding affinities of protein-ligand complexes.
  J Am Chem Soc, 131, 4521-4528.  
19514026 S.Kazemi, D.M.Krüger, F.Sirockin, and H.Gohlke (2009).
Elastic potential grids: accurate and efficient representation of intermolecular interactions for fully flexible docking.
  ChemMedChem, 4, 1264-1268.  
18849972 E.D.Garcin, A.S.Arvai, R.J.Rosenfeld, M.D.Kroeger, B.R.Crane, G.Andersson, G.Andrews, P.J.Hamley, P.R.Mallinder, D.J.Nicholls, S.A.St-Gallay, A.C.Tinker, N.P.Gensmantel, A.Mete, D.R.Cheshire, S.Connolly, D.J.Stuehr, A.Aberg, A.V.Wallace, J.A.Tainer, and E.D.Getzoff (2008).
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
  Nat Chem Biol, 4, 700-707.
PDB codes: 3e65 3e67 3e68 3e6l 3e6n 3e6o 3e6t 3e7g 3e7i 3e7m 3e7s 3e7t 3eah 3eai 3ebd 3ebf 3ej8
18300247 J.G.Olsen, L.Pedersen, C.L.Christensen, O.Olsen, and A.Henriksen (2008).
Barley aldose reductase: structure, cofactor binding, and substrate recognition in the aldo/keto reductase 4C family.
  Proteins, 71, 1572-1581.
PDB codes: 2bgq 2bgs 2vdg
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.  
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.  
  18007059 E.Kiyota, Sousa, M.L.Dos Santos, A.da Costa Lima, M.Menossi, J.A.Yunes, and R.Aparicio (2007).
Crystallization and preliminary X-ray diffraction analysis of maize aldose reductase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 990-992.  
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
16699182 D.E.Danley (2006).
Crystallization to obtain protein-ligand complexes for structure-aided drug design.
  Acta Crystallogr D Biol Crystallogr, 62, 569-575.  
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.  
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
16532451 M.Y.Mizutani, Y.Takamatsu, T.Ichinose, K.Nakamura, and A.Itai (2006).
Effective handling of induced-fit motion in flexible docking.
  Proteins, 63, 878-891.  
16391048 R.Machielsen, A.R.Uria, S.W.Kengen, and J.van der Oost (2006).
Production and characterization of a thermostable alcohol dehydrogenase that belongs to the aldo-keto reductase superfamily.
  Appl Environ Microbiol, 72, 233-238.  
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
15456251 A.M.Ferrari, B.Q.Wei, L.Costantino, and B.K.Shoichet (2004).
Soft docking and multiple receptor conformations in virtual screening.
  J Med Chem, 47, 5076-5084.  
15162486 C.A.Sotriffer, O.Krämer, and G.Klebe (2004).
Probing flexibility and "induced-fit" phenomena in aldose reductase by comparative crystal structure analysis and molecular dynamics simulations.
  Proteins, 56, 52-66.  
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.  
12007809 E.Y.Jeong, I.S.Kim, and H.Lee (2002).
Identification of lysine-78 as an essential residue in the Saccharomyces cerevisiae xylose reductase.
  FEMS Microbiol Lett, 209, 223-228.  
12183464 I.Cecconi, A.Scaloni, G.Rastelli, M.Moroni, P.G.Vilardo, L.Costantino, M.Cappiello, D.Garland, D.Carper, J.M.Petrash, A.Del Corso, and U.Mura (2002).
Oxidative modification of aldose reductase induced by copper ion. Definition of the metal-protein interaction mechanism.
  J Biol Chem, 277, 42017-42027.  
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
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.  
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.  
  10493576 M.Young, K.Kirshenbaum, K.A.Dill, and S.Highsmith (1999).
Predicting conformational switches in proteins.
  Protein Sci, 8, 1752-1764.  
11139842 P.J.Oates, and B.L.Mylari (1999).
Aldose reductase inhibitors: therapeutic implications for diabetic complications.
  Expert Opin Investig Drugs, 8, 2095-2119.  
10584067 P.Várnai, W.G.Richards, and P.D.Lyne (1999).
Modelling the catalytic reaction in human aldose reductase.
  Proteins, 37, 218-227.  
10089480 V.Lamour, P.Barth, H.Rogniaux, A.Poterszman, E.Howard, A.Mitschler, A.Van Dorsselaer, A.Podjarny, and D.Moras (1999).
Production of crystals of human aldose reductase with very high resolution diffraction.
  Acta Crystallogr D Biol Crystallogr, 55, 721-723.  
9730277 H.Lee (1998).
The structure and function of yeast xylose (aldose) reductases.
  Yeast, 14, 977-984.  
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.  
9384557 S.E.Zographos, N.G.Oikonomakos, K.E.Tsitsanou, D.D.Leonidas, E.D.Chrysina, V.T.Skamnaki, H.Bischoff, S.Goldmann, K.A.Watson, and L.N.Johnson (1997).
The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor.
  Structure, 5, 1413-1425.
PDB codes: 1amv 2amv
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.