1US0

Human Aldose Reductase in complex with NADP+ and the inhibitor IDD594 at 0.66 Angstrom


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.66 Å
  • R-Value Free: 0.103 
  • R-Value Observed: 0.094 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Ultrahigh Resolution Drug Design I: Details of Interactions in Human Aldose Reductase-Inhibitor Complex at 0.66 A.

Howard, E.I.Sanishvili, R.Cachau, R.E.Mitschler, A.Chevrier, B.Barth, P.Lamour, V.Van Zandt, M.Sibley, E.Bon, C.Moras, D.Schneider, T.R.Joachimiak, A.Podjarny, A.

(2004) Proteins 55: 792

  • DOI: https://doi.org/10.1002/prot.20015
  • Primary Citation of Related Structures:  
    1US0

  • PubMed Abstract: 

    The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] 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.


  • Organizational Affiliation

    Laboratoire de Génomique et de Biologie Structurales, UMR 7104 du CNRS, IGBMC, Illkirch, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALDOSE REDUCTASE316Homo sapiensMutation(s): 0 
EC: 1.1.1.21
UniProt & NIH Common Fund Data Resources
Find proteins for P15121 (Homo sapiens)
Explore P15121 
Go to UniProtKB:  P15121
PHAROS:  P15121
GTEx:  ENSG00000085662 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15121
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
LDT BindingDB:  1US0 IC50: min: 3, max: 30 (nM) from 2 assay(s)
-TΔS: min: -2.26e+1, max: 7.99 (kJ/mol) from 3 assay(s)
ΔH: -4.62e+1 (kJ/mol) from 1 assay(s)
ΔG: min: -4.09e+1, max: -3.13e+1 (kJ/mol) from 4 assay(s)
Binding MOAD:  1US0 IC50: 30 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.66 Å
  • R-Value Free: 0.103 
  • R-Value Observed: 0.094 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.28α = 90
b = 66.59β = 92.4
c = 47.26γ = 90
Software Package:
Software NamePurpose
SHELXL-97refinement
DENZOdata reduction
SCALEPACKdata scaling
SHELXLphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-05-07
    Type: Initial release
  • Version 1.1: 2014-03-05
    Changes: Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Other, Version format compliance
  • Version 1.2: 2019-05-22
    Changes: Advisory, Data collection, Other, Refinement description