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PDBsum entry 5cgj
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Protein binding
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PDB id
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5cgj
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PDB id:
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| Name: |
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Protein binding
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Title:
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Crystal structure of murine keap1 in complex with ra839, a non- covalent small-molecule binder to keap1 and selective activator of nrf2 signalling.
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Structure:
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Kelch-like ech-associated protein 1. Chain: a. Fragment: keap1-dc, residues 309-624. Synonym: cytosolic inhibitor of nrf2,inrf2. Engineered: yes
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Gene: keap1, inrf2, kiaa0132. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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3.36Å
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R-factor:
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0.141
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R-free:
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0.226
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Authors:
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S.Schimanski-Breves,P.Loenze,C.K.Engel
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Key ref:
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A.F.Winkel
et al.
(2015).
Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling.
J Biol Chem,
290,
28446-28455.
PubMed id:
DOI:
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Date:
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09-Jul-15
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Release date:
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21-Oct-15
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PROCHECK
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Headers
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References
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Q9Z2X8
(KEAP1_MOUSE) -
Kelch-like ECH-associated protein 1 from Mus musculus
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Seq:
Struc:
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624 a.a.
290 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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J Biol Chem
290:28446-28455
(2015)
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PubMed id:
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Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling.
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A.F.Winkel,
C.K.Engel,
D.Margerie,
A.Kannt,
H.Szillat,
H.Glombik,
C.Kallus,
S.Ruf,
S.Güssregen,
J.Riedel,
A.W.Herling,
A.von Knethen,
A.Weigert,
B.Brüne,
D.Schmoll.
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ABSTRACT
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The activation of the transcription factor NF-E2-related factor 2 (Nrf2)
maintains cellular homeostasis in response to oxidative stress by the regulation
of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is
inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein
1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl)
sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small
molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1
with a Kd of ∼6 μm, as demonstrated by x-ray co-crystallization and
isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 μm
RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages.
Canonical pathway mapping of these probe sets revealed an activation of pathways
linked with Nrf2 signaling. These pathways were also activated after the
activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only
two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by
either silencing of Keap1 expression or by the reactive compound
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839
prevented the induction of both inducible nitric-oxide synthase expression and
nitric oxide release in response to lipopolysaccharides in macrophages. In mice,
RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective
inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the
biology of Nrf2.
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Links
