2NVC

Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Evidence for a novel binding site conformer of aldose reductase in ligand-bound state

Steuber, H.Zentgraf, M.La Motta, C.Sartini, S.Heine, A.Klebe, G.

(2007) J Mol Biol 369: 186-197

  • DOI: https://doi.org/10.1016/j.jmb.2007.03.021
  • Primary Citation of Related Structures:  
    2NVC, 2NVD

  • PubMed Abstract: 

    Human aldose reductase (ALR2) has evolved as a promising therapeutic target for the treatment of diabetic long-term complications. The binding site of this enzyme possesses two main subpockets: the catalytic anion-binding site and the hydrophobic specificity pocket. The latter can be observed in the open or closed state, depending on the bound ligand. Thus, it exhibits a pronounced capability for induced-fit adaptations, whereas the catalytic pocket exhibits rigid properties throughout all known crystal structures. Here, we determined two ALR2 crystal structures at 1.55 and 1.65 A resolution, each complexed with an inhibitor of the recently described naphtho[1,2-d]isothiazole acetic acid series. In contrast to the original design hypothesis based on the binding mode of tolrestat (1), both inhibitors leave the specificity pocket in the closed state. Unexpectedly, the more potent ligand (2) extends the catalytic pocket by opening a novel subpocket. Access to this novel subpocket is mainly attributed to the rotation of an indole moiety of Trp 20 by about 35 degrees . The newly formed subpocket provides accommodation of the naphthyl portion of the ligand. The second inhibitor, 3, differs from 2 only by an extended glycolic ester functionality added to one of its carboxylic groups. However, despite this slight structural modification, the binding mode of 3 differs dramatically from that of the first inhibitor, but provokes less pronounced induced-fit adaptations of the binding cavity. Thus, a novel binding site conformation has been identified in a region where previous complex structures suggested only low adaptability of the binding pocket. Furthermore, the two ligand complexes represent an impressive example of how the slight change of a chemically extended side-chain at a given ligand scaffold can result in a dramatically altered binding mode. In addition, our study emphasizes the importance of crystal structure analysis for the translation of affinity data into structure-activity relationships.


  • 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
ITA
Query on ITA

Download Ideal Coordinates CCD File 
C [auth A]{4-[(CARBOXYMETHOXY)CARBONYL]-3,3-DIOXIDO-1-OXONAPHTHO[1,2-D]ISOTHIAZOL-2(1H)-YL}ACETIC ACID
C16 H11 N O9 S
IXLBOIRSEDMRPI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ITA Binding MOAD:  2NVC IC50: 140 (nM) from 1 assay(s)
BindingDB:  2NVC IC50: 550 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.95α = 76.24
b = 47.09β = 77.16
c = 46.87γ = 67.82
Software Package:
Software NamePurpose
SHELXmodel building
SHELXL-97refinement
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-04-24
    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