4LB3

Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.80 Å
  • R-Value Free: 0.131 
  • R-Value Work: 0.131 
  • R-Value Observed: 0.131 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Modulation of aldose reductase inhibition by halogen bond tuning.

Fanfrlik, J.Kolar, M.Kamlar, M.Hurny, D.Ruiz, F.X.Cousido-Siah, A.Mitschler, A.Rezac, J.Munusamy, E.Lepsik, M.Matejicek, P.Vesely, J.Podjarny, A.Hobza, P.

(2013) ACS Chem Biol 8: 2484-2492

  • DOI: https://doi.org/10.1021/cb400526n
  • Primary Citation of Related Structures:  
    4LAU, 4LAZ, 4LB3, 4LB4, 4LBR, 4LBS

  • PubMed Abstract: 

    In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes.


  • Organizational Affiliation

    Institute of Organic Chemistry and Biochemistry and Gilead Science Research Center, Academy of Sciences of the Czech Republic , Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aldose reductase316Homo 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 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
M15
Query on M15

Download Ideal Coordinates CCD File 
C [auth A]{5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid
C16 H12 Cl F I N O4
ATJRPHWOUZQPIU-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
M15 BindingDB:  4LB3 IC50: 190 (nM) from 1 assay(s)
Binding MOAD:  4LB3 IC50: 190 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.80 Å
  • R-Value Free: 0.131 
  • R-Value Work: 0.131 
  • R-Value Observed: 0.131 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.244α = 90
b = 66.845β = 92.46
c = 47.244γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-30
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description