3T42

Human aldose reductase in complex with a nitrile-containing IDD inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.28 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.152 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Electrostatic Fields near the Active Site of Human Aldose Reductase: 2. New Inhibitors and Complications Caused by Hydrogen Bonds.

Xu, L.Cohen, A.E.Boxer, S.G.

(2011) Biochemistry 50: 8311-8322

  • DOI: https://doi.org/10.1021/bi200930f
  • Primary Citation of Related Structures:  
    3T42

  • PubMed Abstract: 

    Vibrational Stark effect spectroscopy was used to measure electrostatic fields in the hydrophobic region of the active site of human aldose reductase (hALR2). A new nitrile-containing inhibitor was designed and synthesized, and the X-ray structure of its complex, along with cofactor NADP(+), with wild-type hALR2 was determined at 1.3 Å resolution. The nitrile is found to be in the proximity of T113, consistent with a hydrogen bond interaction. Two vibrational absorption peaks were observed at room temperature in the nitrile region when the inhibitor binds to wild-type hALR2, indicating that the nitrile probe experiences two different microenvironments, and these could be empirically separated into a hydrogen-bonded and non-hydrogen-bonded population by comparison with the T113A mutant, in which a hydrogen bond to the nitrile is not present. Classical molecular dynamics simulations based on the structure predict a double-peak distribution in protein electric fields projected along the nitrile probe. The interpretation of these two peaks as a hydrogen bond formation-dissociation process between the probe nitrile group and a nearby amino acid side chain is used to explain the observation of two IR bands, and the simulations were used to investigate the molecular details of this conformational change. Hydrogen bonding complicates the simplest analysis of vibrational frequency shifts as being due solely to electrostatic interactions through the vibrational Stark effect, and the consequences of this complication are discussed.


  • Organizational Affiliation

    Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldose reductase319Homo sapiensMutation(s): 0 
Gene Names: AKR1B1ALDR1
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 3 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
3T4
Query on 3T4

Download Ideal Coordinates CCD File 
C [auth A]{5-chloro-2-[(4-cyano-3-nitrobenzyl)carbamoyl]phenoxy}acetic acid
C17 H12 Cl N3 O6
VTRDVRBVJGKWET-UHFFFAOYSA-N
CIT
Query on CIT

Download Ideal Coordinates CCD File 
D [auth A]CITRIC ACID
C6 H8 O7
KRKNYBCHXYNGOX-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3T4 Binding MOAD:  3T42 Ki: 107 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.28 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.152 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.858α = 76.35
b = 46.963β = 77.21
c = 46.907γ = 67.79
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-05
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description