2IKG

Aldose reductase complexed with nitrophenyl-oxadiazol type inhibitor at 1.43 A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.130 
  • R-Value Observed: 0.140 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural and Thermodynamic Study on Aldose Reductase: Nitro-substituted Inhibitors with Strong Enthalpic Binding Contribution

Steuber, H.Heine, A.Klebe, G.

(2007) J Mol Biol 368: 618-638

  • DOI: https://doi.org/10.1016/j.jmb.2006.12.004
  • Primary Citation of Related Structures:  
    2IKG, 2IKH, 2IKI, 2IKJ

  • PubMed Abstract: 

    To prevent diabetic complications derived from enhanced glucose flux via the polyol pathway the development of aldose reductase inhibitors (ARIs) has been established as a promising therapeutic concept. In order to identify novel lead compounds, a virtual screening (VS) was performed successfully suggesting carboxylate-type inhibitors of sub-micromolar to micromolar affinity. Here, we combine a structural characterization of the binding modes observed by X-ray crystallography with isothermal titration calorimetry (ITC) measurements providing insights into the driving forces of inhibitor binding, particularly of the first leads from VS. Characteristic features of this novel inhibitor type include a carboxylate head group connected via an alkyl spacer to a heteroaromatic moiety, which is linked to a further nitro-substituted aromatic portion. The crystal structures of two enzyme-inhibitor complexes have been determined at resolutions of 1.43 A and 1.55 A. Surprisingly, the carboxylic group of the most potent VS lead occupies the catalytic pocket differently compared to the interaction geometry observed in almost all other crystal structures with structurally related ligands and obtained under similar conditions, as an interstitial water molecule is picked up upon ligand binding. The nitro-aromatic moiety of both leads occupies the specificity pocket of the enzyme, however, adopting a different geometry compared to the docking prediction: unexpectedly, the nitro group binds to the bottom of the specificity pocket and provokes remarkable induced-fit adaptations. A peptide group located at the active site orients in such a way that H-bond formation to one nitro group oxygen atom is enabled, whereas a neighbouring tyrosine side-chain performs a slight rotation off from the binding cavity to accommodate the nitro group. Identically constituted ligands, lacking this nitro group, exhibit an affinity drop of one order of magnitude. In addition, thermodynamic data suggest a strongly favourable contribution to binding enthalpy in case the inhibitor is equipped with a nitro group at the corresponding position. To further investigate this phenomenon, we determined crystal structures and thermodynamic data of two similarly constituted IDD-type inhibitors addressing the specificity pocket with either a nitro or halogen-substituted aromatic moiety. As these data suggest, the nitro group provokes the enthalpic contribution, in addition to the H-bond mentioned above, by accepting two "non-classical" H-bonds donated by the aromatic tyrosine side-chain. In summary, this study provides the platform for further structure-guided design hypotheses of novel drug candidates with higher affinity and selectivity.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldose reductase316Homo sapiensMutation(s): 0 
Gene Names: hALR2
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
BTO
Query on BTO

Download Ideal Coordinates CCD File 
C [auth A]4-[3-(3-NITROPHENYL)-1,2,4-OXADIAZOL-5-YL]BUTANOIC ACID
C12 H11 N3 O5
LQQYZJRCWBRIMW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BTO Binding MOAD:  2IKG IC50: 530 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.130 
  • R-Value Observed: 0.140 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.285α = 90
b = 66.745β = 92.59
c = 47.154γ = 90
Software Package:
Software NamePurpose
SHELXmodel building
SHELXL-97refinement
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-05-01
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description