spacer
spacer

PDBsum entry 1us0

Go to PDB code: 
protein ligands links
Oxidoreductase PDB id
1us0
Jmol
Contents
Protein chain
314 a.a. *
Ligands
NDP
LDT
CIT ×2
Waters ×613
* Residue conservation analysis
PDB id:
1us0
Name: Oxidoreductase
Title: Human aldose reductase in complex with NADP+ and the inhibitor idd594 at 0.66 angstrom
Structure: Aldose reductase. Chain: a. Synonym: aldehyde reductase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
0.66Å     R-factor:   0.093     R-free:   0.103
Authors: 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,A.Podjarny
Key ref:
E.I.Howard et al. (2004). Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. Proteins, 55, 792-804. PubMed id: 15146478 DOI: 10.1002/prot.20015
Date:
16-Nov-03     Release date:   07-May-04    
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 1 residue position (black cross)

 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 = NDP)
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   4 terms 
  Biological process     small molecule metabolic process   8 terms 
  Biochemical function     electron carrier activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1002/prot.20015 Proteins 55:792-804 (2004)
PubMed id: 15146478  
 
 
Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.
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, A.Podjarny.
 
  ABSTRACT  
 
The first subatomic resolution structure of a 36 kDa protein [aldose reductase is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Contacts of IDD 594 with AR and NADP^+. (a) 3D view of inhibitor contacts. View of the inhibitor-binding site down the barrel axis with the semitransparent representation of AR surface. The active site cleft (marked A), is occupied by the inhibitor (stick only; color code: C = gray, N = blue, O = red, F = pink, S = orange, Br = green) and surrounded by the catalytic residues His 110, Tyr 48, and the coenzyme NADP^+. The residues within 3.9 Å and NADP^+ are shown (balls and sticks). The specificity pocket between Leu 300, Phe 122, and Trp 111 (marked S) is occupied by the brominated aromatic ring of the inhibitor. (b) Scheme of IDD 594 and its contacts. Red dashed lines show contacts between 3.5 and 3.0 Å, and blue dashed lines show contacts <3.0 Å. The exact values are given in Table IV.
Figure 5.
Figure 5. Model of residues Cys 44 and Ala 45 superimposed with A-weighted Fo-Fc map with omitted hydrogen atoms (a), contoured magenta at at 0.25 e/Å^3 (2.5 ) showing the position of the hydrogen atoms and the bond densities. Model of residues Ser 76 and Lys 77(b), viewed down the C N peptide bond showing the angle of -167.3° stabilized by an H-bond.
 
  The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2004, 55, 792-804) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22259562 K.Sunitha, H.C.Devarajegowda, W.F.Al-Eryani, Y.R.Prasad, and A.U.Kumar (2012).
(2E)-1-(5-Bromo-thio-phen-2-yl)-3-(2,3,4-trimeth-oxy-phen-yl)prop-2-en-1-one.
  Acta Crystallogr Sect E Struct Rep Online, 68, o61.  
21514701 A.M.Katsori, M.Chatzopoulou, K.Dimas, C.Kontogiorgis, A.Patsilinakos, T.Trangas, and D.Hadjipavlou-Litina (2011).
Curcumin analogues as possible anti-proliferative & anti-inflammatory agents.
  Eur J Med Chem, 46, 2722-2735.  
21365086 E.Parisini, P.Metrangolo, T.Pilati, G.Resnati, and G.Terraneo (2011).
Halogen bonding in halocarbon-protein complexes: a structural survey.
  Chem Soc Rev, 40, 2267-2278.  
20558186 G.M.Alushin, D.Jane, and M.L.Mayer (2011).
Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists.
  Neuropharmacology, 60, 126-134.
PDB codes: 2qs1 2qs2 2qs4
20516622 A.Higashiura, T.Kurakane, M.Matsuda, M.Suzuki, K.Inaka, M.Sato, T.Kobayashi, T.Tanaka, H.Tanaka, K.Fujiwara, and A.Nakagawa (2010).
High-resolution X-ray crystal structure of bovine H-protein at 0.88 A resolution.
  Acta Crystallogr D Biol Crystallogr, 66, 698-708.
PDB code: 3klr
20516624 L.Gabison, M.Chiadmi, M.El Hajji, B.Castro, N.Colloc'h, and T.Prangé (2010).
Near-atomic resolution structures of urate oxidase complexed with its substrate and analogues: the protonation state of the ligand.
  Acta Crystallogr D Biol Crystallogr, 66, 714-724.
PDB codes: 3l8w 3l9g 3lbg 3ld4
20069322 Y.K.Jiang (2010).
Molecular docking and 3D-QSAR studies on beta-phenylalanine derivatives as dipeptidyl peptidase IV inhibitors.
  J Mol Model, 16, 1239-1249.  
20428531 Y.Lu, Y.Wang, and W.Zhu (2010).
Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design.
  Phys Chem Chem Phys, 12, 4543-4551.  
20567074 Z.Dauter, M.Jaskolski, and A.Wlodawer (2010).
Impact of synchrotron radiation on macromolecular crystallography: a personal view.
  J Synchrotron Radiat, 17, 433-444.  
  19194016 A.S.Gardberg, M.P.Blakeley, and D.A.Myles (2009).
A preliminary neutron crystallographic study of proteinase K at pD 6.5.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 184-187.  
19966414 A.Urzhumtsev, P.V.Afonine, and P.D.Adams (2009).
On the use of logarithmic scales for analysis of diffraction data.
  Acta Crystallogr D Biol Crystallogr, 65, 1283-1291.  
19586953 E.Oksanen, M.P.Blakeley, F.Bonneté, M.T.Dauvergne, F.Dauvergne, and M.Budayova-Spano (2009).
Large crystal growth by thermal control allows combined X-ray and neutron crystallographic studies to elucidate the protonation states in Aspergillus flavus urate oxidase.
  J R Soc Interface, 6, S599-S610.  
19301313 M.Eisenmann, H.Steuber, M.Zentgraf, M.Altenkämper, R.Ortmann, J.Perruchon, G.Klebe, and M.Schlitzer (2009).
Structure-based optimization of aldose reductase inhibitors originating from virtual screening.
  ChemMedChem, 4, 809-819.
PDB code: 3dn5
19690373 M.J.Schnieders, T.D.Fenn, V.S.Pande, and A.T.Brunger (2009).
Polarizable atomic multipole X-ray refinement: application to peptide crystals.
  Acta Crystallogr D Biol Crystallogr, 65, 952-965.  
19768809 V.B.Chen, I.W.Davis, and D.C.Richardson (2009).
KING (Kinemage, Next Generation): a versatile interactive molecular and scientific visualization program.
  Protein Sci, 18, 2403-2409.  
18453693 B.Guillot, C.Jelsch, A.Podjarny, and C.Lecomte (2008).
Charge-density analysis of a protein structure at subatomic resolution: the human aldose reductase case.
  Acta Crystallogr D Biol Crystallogr, 64, 567-588.  
18323618 E.Nishibori, T.Nakamura, M.Arimoto, S.Aoyagi, H.Ago, M.Miyano, T.Ebisuzaki, and M.Sakata (2008).
Application of maximum-entropy maps in the accurate refinement of a putative acylphosphatase using 1.3 A X-ray diffraction data.
  Acta Crystallogr D Biol Crystallogr, 64, 237-247.  
18250329 M.P.Blakeley, F.Ruiz, R.Cachau, I.Hazemann, F.Meilleur, A.Mitschler, S.Ginell, P.Afonine, O.N.Ventura, A.Cousido-Siah, M.Haertlein, A.Joachimiak, D.Myles, and A.Podjarny (2008).
Quantum model of catalysis based on a mobile proton revealed by subatomic x-ray and neutron diffraction studies of h-aldose reductase.
  Proc Natl Acad Sci U S A, 105, 1844-1848.
PDB codes: 2qxw 2r24
18156668 N.Niimura, and R.Bau (2008).
Neutron protein crystallography: beyond the folding structure of biological macromolecules.
  Acta Crystallogr A, 64, 12-22.  
17096417 A.A.Rashin, and A.H.Rashin (2007).
Surface hydrophobic groups, stability, and flip-flopping in lattice proteins.
  Proteins, 66, 321-341.  
17242509 A.Volkov, M.Messerschmidt, and P.Coppens (2007).
Improving the scattering-factor formalism in protein refinement: application of the University at Buffalo Aspherical-Atom Databank to polypeptide structures.
  Acta Crystallogr D Biol Crystallogr, 63, 160-170.  
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.  
17642517 H.U.Ahmed, M.P.Blakeley, M.Cianci, D.W.Cruickshank, J.A.Hubbard, and J.R.Helliwell (2007).
The determination of protonation states in proteins.
  Acta Crystallogr D Biol Crystallogr, 63, 906-922.
PDB codes: 2uu8 2uuf 2uuj 2uuk 2yz4
18084073 J.Wang, M.Dauter, R.Alkire, A.Joachimiak, and Z.Dauter (2007).
Triclinic lysozyme at 0.65 A resolution.
  Acta Crystallogr D Biol Crystallogr, 63, 1254-1268.
PDB code: 2vb1
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
17452786 M.Jaskolski, M.Gilski, Z.Dauter, and A.Wlodawer (2007).
Stereochemical restraints revisited: how accurate are refinement targets and how much should protein structures be allowed to deviate from them?
  Acta Crystallogr D Biol Crystallogr, 63, 611-620.  
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.  
16897039 F.Meilleur, D.A.Myles, and M.P.Blakeley (2006).
Neutron Laue macromolecular crystallography.
  Eur Biophys J, 35, 611-620.  
16371706 G.Rosenbaum, R.W.Alkire, G.Evans, F.J.Rotella, K.Lazarski, R.G.Zhang, S.L.Ginell, N.Duke, I.Naday, J.Lazarz, M.J.Molitsky, L.Keefe, J.Gonczy, L.Rock, R.Sanishvili, M.A.Walsh, E.Westbrook, and A.Joachimiak (2006).
The Structural Biology Center 19ID undulator beamline: facility specifications and protein crystallographic results.
  J Synchrotron Radiat, 13, 30-45.  
16552136 J.Hakanpää, M.Linder, A.Popov, A.Schmidt, and J.Rouvinen (2006).
Hydrophobin HFBII in detail: ultrahigh-resolution structure at 0.75 A.
  Acta Crystallogr D Biol Crystallogr, 62, 356-367.
PDB code: 2b97
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
16622654 M.P.Blakeley, A.Mitschler, I.Hazemann, F.Meilleur, D.A.Myles, and A.Podjarny (2006).
Comparison of hydrogen determination with X-ray and neutron crystallography in a human aldose reductase-inhibitor complex.
  Eur Biophys J, 35, 577-583.  
17139089 T.Petrova, S.Ginell, A.Mitschler, I.Hazemann, T.Schneider, A.Cousido, V.Y.Lunin, A.Joachimiak, and A.Podjarny (2006).
Ultrahigh-resolution study of protein atomic displacement parameters at cryotemperatures obtained with a helium cryostat.
  Acta Crystallogr D Biol Crystallogr, 62, 1535-1544.
PDB codes: 2i16 2i17
15624213 A.A.Rashin, and A.H.Rashin (2005).
Lattice models, packing density, and Boltzmann-like distribution of cavities in proteins.
  Proteins, 58, 547-559.  
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.  
15983423 H.Bönisch, C.L.Schmidt, P.Bianco, and R.Ladenstein (2005).
Ultrahigh-resolution study on Pyrococcus abyssi rubredoxin. I. 0.69 A X-ray structure of mutant W4L/R5S.
  Acta Crystallogr D Biol Crystallogr, 61, 990.
PDB codes: 1yk4 1yk5
16204895 I.Hazemann, M.T.Dauvergne, M.P.Blakeley, F.Meilleur, M.Haertlein, A.Van Dorsselaer, A.Mitschler, D.A.Myles, and A.Podjarny (2005).
High-resolution neutron protein crystallography with radically small crystal volumes: application of perdeuteration to human aldose reductase.
  Acta Crystallogr D Biol Crystallogr, 61, 1413-1417.  
15525703 M.P.Blakeley, A.J.Kalb, J.R.Helliwell, and D.A.Myles (2004).
The 15-K neutron structure of saccharide-free concanavalin A.
  Proc Natl Acad Sci U S A, 101, 16405-16410.  
15557000 P.Auffinger, F.A.Hays, E.Westhof, and P.S.Ho (2004).
Halogen bonds in biological molecules.
  Proc Natl Acad Sci U S A, 101, 16789-16794.  
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.