1PWL

Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.125 
  • R-Value Work: 0.099 
  • R-Value Observed: 0.100 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

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

El-Kabbani, O.Darmanin, C.Schneider, T.R.Hazemann, I.Ruiz, F.Oka, M.Joachimiak, A.Schulze-Briese, C.Tomizaki, T.Mitschler, A.Podjarny, A.

(2004) Proteins 55: 805-813

  • DOI: https://doi.org/10.1002/prot.20001
  • Primary Citation of Related Structures:  
    1PWL, 1PWM

  • PubMed Abstract: 

    The X-ray structures of human aldose reductase holoenzyme in complex with the inhibitors Fidarestat (SNK-860) and Minalrestat (WAY-509) were determined at atomic resolutions of 0.92 A and 1.1 A, respectively. The hydantoin and succinimide moieties of the inhibitors interacted with the conserved anion-binding site located between the nicotinamide ring of the coenzyme and active site residues Tyr48, His110, and Trp111. Minalrestat's hydrophobic isoquinoline ring was bound in an adjacent pocket lined by residues Trp20, Phe122, and Trp219, with the bromo-fluorobenzyl group inside the "specificity" pocket. The interactions between Minalrestat's bromo-fluorobenzyl group and the enzyme include the stacking against the side-chain of Trp111 as well as hydrogen bonding distances with residues Leu300 and Thr113. The carbamoyl group in Fidarestat formed a hydrogen bond with the main-chain nitrogen atom of Leu300. The atomic resolution refinement allowed the positioning of hydrogen atoms and accurate determination of bond lengths of the inhibitors, coenzyme NADP+ and active-site residue His110. The 1'-position nitrogen atom in the hydantoin and succinimide moieties of Fidarestat and Minalrestat, respectively, form a hydrogen bond with the Nepsilon2 atom of His 110. For Fidarestat, the electron density indicated two possible positions for the H-atom in this bond. Furthermore, both native and anomalous difference maps indicated the replacement of a water molecule linked to His110 by a Cl-ion. These observations suggest a mechanism in which Fidarestat is bound protonated and becomes negatively charged by donating the proton to His110, which may have important implications on drug design.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, Australia.


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 
C [auth A]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
BFI
Query on BFI

Download Ideal Coordinates CCD File 
B [auth A]2[4-BROMO-2-FLUOROPHENYL)METHYL]-6-FLUOROSPIRO[ISOQUINOLINE-4-(1H),3'-PYRROLIDINE]-1,2',3,5'(2H)-TETRONE
C19 H11 Br F2 N2 O4
BMHZAHGTGIZZCT-LJQANCHMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BFI BindingDB:  1PWL Kd: 5.5 (nM) from 1 assay(s)
IC50: min: 9, max: 73 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.125 
  • R-Value Work: 0.099 
  • R-Value Observed: 0.100 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.019α = 75.71
b = 47.128β = 67.48
c = 47.367γ = 76.75
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
X-PLORmodel building
SHELXL-97refinement
X-PLORphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-02-24
    Type: Initial release
  • Version 1.1: 2007-10-16
    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