kelch like ECH-associated protein 1

Target id: 2757

Nomenclature: kelch like ECH-associated protein 1

Family: Kelch-like proteins

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     kelch like ECH-associated protein 1 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 624 19p13.2 KEAP1 kelch like ECH associated protein 1
Mouse - 624 9 A3 Keap1 kelch-like ECH-associated protein 1
Rat - 620 8q13 Keap1 Kelch-like ECH-associated protein 1
Previous and Unofficial Names
INrf2 | kelch-like ECH-associated protein 1
Database Links
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
Nrf2 peptide [PMID: 23647822] Hs Binding 7.5 pIC50 4
pIC50 7.5 (IC50 3.3x10-8 M) [4]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CPUY192018 Hs Binding 7.4 pKd 3
pKd 7.4 (Kd 3.98x10-8 M) [3]
Description: Measuerd using a isothermal titration calorimetry (ITC) assay.
CPUY192018 Hs Binding 7.8 pIC50 2
pIC50 7.8 (IC50 1.44x10-8 M) [2]
Description: Measured using a fluorescence polarisation assay.
bardoxolone Hs Binding >7.0 pIC50 1
pIC50 >7.0 (IC50 <1x10-7 M) [1]
Description: Measuring inhibition of KEAP1 binding to Cul3 using an AlphaScreen bead-based proximity assay.
Immunopharmacology Comments
Nrf2-responsive genes have an ARE (antioxidant responsive element) in their promoter sequences, and play important roles in the cellular defense system and regulation of the response to oxidative stress. Nrf2 binding to AREs induces transcription of genes with detoxification, antioxidant, cytoprotective and anti-inflammatory functions. Small molecule drug-like compounds that inhibit the KEAP1-Nrf2 protein-protein interaction (a.k.a. Nrf2 activators) are being developed for their potential anti-inflammatory action. The approved MS prodrug dimethyl fumarate exploits this molecular mechanism.
Immuno Process Associations
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  protein ubiquitination (GO:0016567) IDA
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  cellular response to interleukin-4 (GO:0071353) IEA
References: 
General Comments
The KEAP1 protein binds to and inhibits the transcriptional activity of NF-E2-related factor 2 (Nrf2; NFE2L2; Q16236).

References

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1. Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK et al.. (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE9 (6): e98896. [PMID:24896564]

2. Jiang ZY, Xu LL, Lu MC, Chen ZY, Yuan ZW, Xu XL, Guo XK, Zhang XJ, Sun HP, You QD. (2015) Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor. J. Med. Chem.58 (16): 6410-21. [PMID:26258437]

3. Lu MC, Ji JA, Jiang YL, Chen ZY, Yuan ZW, You QD, Jiang ZY. (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep6: 26585. [PMID:27215610]

4. Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H et al.. (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg. Med. Chem.21 (14): 4011-9. [PMID:23647822]

How to cite this page

Kelch-like proteins: kelch like ECH-associated protein 1. Last modified on 23/11/2017. Accessed on 18/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2757.