1T40

Crystal structure of human aldose reductase complexed with NADP and IDD552 at ph 5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.159 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

The crystallographic structure of the aldose reductase-IDD552 complex shows direct proton donation from tyrosine 48.

Ruiz, F.Hazemann, I.Mitschler, A.Joachimiak, A.Schneider, T.Karplus, M.Podjarny, A.

(2004) Acta Crystallogr D Biol Crystallogr 60: 1347-1354

  • DOI: https://doi.org/10.1107/S0907444904011370
  • Primary Citation of Related Structures:  
    1T40, 1T41

  • PubMed Abstract: 

    The X-ray crystal structure of human aldose reductase (ALR2) in complex with the inhibitor IDD552 was determined using crystals obtained from two crystallization conditions with different pH values (pH 5 and 8). In both structures the charged carboxylic head of the inhibitor binds to the active site, making hydrogen-bond interactions with His110 and Tyr48 and electrostatic interactions with NADP+. There is an important difference between the two structures: the observation of a double conformation of the carboxylic acid moiety of the inhibitor at pH 8, with one water molecule interacting with the main configuration. This is the first time that a water molecule has been observed deep inside the ALR2 active site. Furthermore, in the configuration with the lower occupancy factor the difference electron-density map shows a clear peak (2.5sigma) for the H atom in the hydrogen bond between the inhibitor's carboxylic acid and the Tyr48 side-chain O atom. The position of this peak implies that this H atom is shared between both O atoms, indicating possible direct proton transfer from this residue to the inhibitor. This fact agrees with the model of the catalytic mechanism, in which the proton is donated by the Tyr48 hydroxyl to the substrate. These observations are useful both in drug design and in understanding the ALR2 mechanism.


  • Organizational Affiliation

    UPR de Biologie Structurale, IGBMC, CNRS INSERM ULP, 1 Rue Laurent Fries, BP 163, 67404 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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
B [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
ID5
Query on ID5

Download Ideal Coordinates CCD File 
C [auth A][5-FLUORO-2-({[(4,5,7-TRIFLUORO-1,3-BENZOTHIAZOL-2-YL)METHYL]AMINO}CARBONYL)PHENOXY]ACETIC ACID
C17 H10 F4 N2 O4 S
ZCAGEXZTORJQDZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ID5 BindingDB:  1T40 IC50: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.159 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50α = 90
b = 67.24β = 92.5
c = 47.78γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-08-03
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references, Derived calculations