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Oxidoreductase PDB id
1az1
Jmol
Contents
Protein chain
314 a.a. *
Ligands
NAP
ALR ×2
Waters ×220
* Residue conservation analysis
PDB id:
1az1
Name: Oxidoreductase
Title: Alrestatin bound to c298a/w219y mutant human aldose reductase
Structure: Aldose reductase. Chain: a. Engineered: yes. Mutation: yes. Other_details: alrestatin, c14no4h8
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Gene: alr2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.80Å     R-factor:   0.177     R-free:   0.232
Authors: D.H.T.Harrison,K.M.Bohren,G.A.Petsko,D.Ringe,K.H.Gabbay
Key ref:
D.H.Harrison et al. (1997). The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant. Biochemistry, 36, 16134-16140. PubMed id: 9405046 DOI: 10.1021/bi9717136
Date:
24-Nov-97     Release date:   18-Mar-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P15121  (ALDR_HUMAN) -  Aldose reductase
Seq:
Struc: 		316 a.a.
314 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.21  - Aldehyde reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Alditol + NAD(P)(+) = aldose + NAD(P)H
Alditol
 +
NAD(P)(+)
Bound ligand (Het Group name = NAP)
corresponds exactly 		= aldose
 + NAD(P)H
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   3 terms 
  Biological process     response to stress   4 terms 
  Biochemical function     electron carrier activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi9717136 Biochemistry 36:16134-16140 (1997)
PubMed id: 9405046  
 
 
The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant.
D.H.Harrison, K.M.Bohren, G.A.Petsko, D.Ringe, K.H.Gabbay.
 
  ABSTRACT  
 
It is generally expected that only one inhibitor molecule will bind to an enzyme active site. In fact, specific drug design theories depend upon this assumption. Here, we report the binding of two molecules of an inhibitor to the same active site which we observed in the 1.8 A resolution structure of the drug Alrestatin bound to a mutant of human aldose reductase. The two molecules of Alrestatin bind to the active site in a stacked arrangement (a double-decker). This stack positions the carboxylic acid of one drug molecule near the NADP+ cofactor at a previously determined anion binding site and the carboxylic acid of the second drug molecule near the carboxy-terminal tail of the enzyme. We propose that interactions of inhibitors with the carboxy-terminal loop of aldose reductase are critical for the development of inhibitors that are able to discriminate between aldose reductase and other members of the aldo-keto reductase superfamily. This finding suggests a new direction for the introduction of specificity to aldose reductase-targeted drugs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18645237 N.Trabelsi, P.Petit, C.Manigand, B.Langlois d'Estaintot, T.Granier, J.Chaudière, and B.Gallois (2008).
Structural evidence for the inhibition of grape dihydroflavonol 4-reductase by flavonols.
  Acta Crystallogr D Biol Crystallogr, 64, 883-891.
PDB codes: 3bxx 3c1t
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
  16880544 B.K.Biswal, K.Au, M.M.Cherney, C.Garen, and M.N.James (2006).
The molecular structure of Rv2074, a probable pyridoxine 5'-phosphate oxidase from Mycobacterium tuberculosis, at 1.6 angstroms resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 735-742.
PDB code: 2asf
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
16262561 S.Bruno, D.Cattaneo, N.Perico, and G.Remuzzi (2005).
Emerging drugs for diabetic nephropathy.
  Expert Opin Emerg Drugs, 10, 747-771.  
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.  
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
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.  
12867417 S.Reinelt, E.Hofmann, T.Gerharz, M.Bott, and D.R.Madden (2003).
The structure of the periplasmic ligand-binding domain of the sensor kinase CitA reveals the first extracellular PAS domain.
  J Biol Chem, 278, 39189-39196.
PDB code: 1p0z
12554940 T.Kinoshita, N.Nishio, I.Nakanishi, A.Sato, and T.Fujii (2003).
Structure of bovine adenosine deaminase complexed with 6-hydroxy-1,6-dihydropurine riboside.
  Acta Crystallogr D Biol Crystallogr, 59, 299-303.
PDB code: 1krm
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
11354001 Q.Ye, D.Hyndman, N.Green, X.Li, B.Korithoski, Z.Jia, and T.G.Flynn (2001).
Crystal structure of an aldehyde reductase Y50F mutant-NADP complex and its implications for substrate binding.
  Proteins, 44, 12-19.  
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.  
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.  
  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.  
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.