4L7C

Structure of keap1 kelch domain with 2-{[(1S)-2-{[(1R,2S)-2-(1H-tetrazol-5-yl)cyclohexyl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}-1H-isoindole-1,3(2H)-dione


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.265 
  • R-Value Observed: 0.266 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex.

Jnoff, E.Albrecht, C.Barker, J.J.Barker, O.Beaumont, E.Bromidge, S.Brookfield, F.Brooks, M.Bubert, C.Ceska, T.Corden, V.Dawson, G.Duclos, S.Fryatt, T.Genicot, C.Jigorel, E.Kwong, J.Maghames, R.Mushi, I.Pike, R.Sands, Z.A.Smith, M.A.Stimson, C.C.Courade, J.P.

(2014) ChemMedChem 9: 699-705

  • DOI: https://doi.org/10.1002/cmdc.201300525
  • Primary Citation of Related Structures:  
    4L7B, 4L7C, 4L7D, 4N1B

  • PubMed Abstract: 

    An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.


  • Organizational Affiliation

    UCB Pharma, UCB NewMedicines, Chemin du Foriest, 1420 Braine-l'Alleud (Belgium). eric.jnoff@ucb.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kelch-like ECH-associated protein 1
A, B, C
300Homo sapiensMutation(s): 1 
Gene Names: KEAP1INRF2KIAA0132KLHL19
UniProt & NIH Common Fund Data Resources
Find proteins for Q14145 (Homo sapiens)
Explore Q14145 
Go to UniProtKB:  Q14145
PHAROS:  Q14145
GTEx:  ENSG00000079999 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ14145
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1VW Binding MOAD:  4L7C IC50: 7400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.265 
  • R-Value Observed: 0.266 
  • Space Group: P 21 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.29α = 90
b = 125.61β = 90
c = 132.63γ = 90
Software Package:
Software NamePurpose
GO.COMdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-19
    Type: Initial release
  • Version 1.1: 2014-04-23
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description