5FNT

Structure of the Keap1 Kelch domain in complex with a small molecule inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Mono-Acidic Inhibitors of the Kelch-Like Ech-Associated Protein 1 : Nuclear Factor Erythroid 2-Related Factor 2 (Keap1:Nrf2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

Davies, T.G.Wixted, W.E.Coyle, J.E.Griffiths-Jones, C.Hearn, K.Mcmenamin, R.L.Norton, D.Rich, S.J.Richardson, C.Saxty, G.Willems, H.M.G.Woolford, A.J.Cottom, J.E.Kou, J.Yonchuk, J.G.Feldser, H.G.Sanchez, Y.Foley, J.P.Bolognese, B.J.Logan, G.A.Podolin, P.L.Yan, H.Callahan, J.F.Heightman, T.D.Kerns, J.K.

(2016) J Med Chem 59: 3991

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00228
  • Primary Citation of Related Structures:  
    5FNQ, 5FNR, 5FNS, 5FNT, 5FNU, 5FZJ, 5FZN

  • PubMed Abstract: 

    KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.


  • Organizational Affiliation

    Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
KELCH-LIKE ECH-ASSOCIATED PROTEIN 1304Mus musculusMutation(s): 0 
UniProt
Find proteins for Q9Z2X8 (Mus musculus)
Explore Q9Z2X8 
Go to UniProtKB:  Q9Z2X8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Z2X8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0PL
Query on 0PL

Download Ideal Coordinates CCD File 
C [auth A](3S)-3-{4-Chloro-3-[(N-methylbenzenesulfonamido) methyl]phenyl}-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid
C24 H23 Cl N4 O4 S
NICLDNFOUWEYPY-FQEVSTJZSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
B [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
0PL BindingDB:  5FNT Kd: 670 (nM) from 1 assay(s)
IC50: min: 270, max: 550 (nM) from 2 assay(s)
Binding MOAD:  5FNT Kd: 670 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.349α = 90
b = 103.349β = 90
c = 56.36γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-13
    Type: Initial release
  • Version 1.1: 2016-05-11
    Changes: Database references
  • Version 2.0: 2018-04-04
    Changes: Atomic model, Data collection
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description