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PDBsum entry 5fns
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Transcription
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PDB id
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5fns
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PDB id:
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Transcription
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Title:
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Structure of the keap1 kelch domain in complex with a small molecule inhibitor.
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Structure:
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Kelch-like ech-associated protein 1. Chain: a. Fragment: kelch domain, residues 322-624. Synonym: keap1, cytosolic inhibitor of nrf2, inrf2. Engineered: yes
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Source:
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Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.79Å
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R-factor:
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0.178
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R-free:
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0.212
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Authors:
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T.G.Davies,W.E.Wixted,J.E.Coyle,C.Griffiths-Jones,K.Hearn, R.Mcmenamin,D.Norton,S.J.Rich,C.Richardson,G.Saxty,H.M.G.Willems, A.J.Woolford,J.E.Cottom,J.Kou,J.G.Yonchuk,H.G.Feldser,Y.Sanchez, J.P.Foley,B.J.Bolognese,G.Logan,P.L.Podolin,H.Yan,J.F.Callahan, T.D.Heightman,J.K.Kerns
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Key ref:
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T.G.Davies
et al.
(2016).
Monoacidic 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.
J Med Chem,
59,
3991-4006.
PubMed id:
DOI:
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Date:
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16-Nov-15
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Release date:
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13-Apr-16
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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.
289 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 Med Chem
59:3991-4006
(2016)
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PubMed id:
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Monoacidic 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.
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T.G.Davies,
W.E.Wixted,
J.E.Coyle,
C.Griffiths-Jones,
K.Hearn,
R.McMenamin,
D.Norton,
S.J.Rich,
C.Richardson,
G.Saxty,
H.M.Willems,
A.J.Woolford,
J.E.Cottom,
J.P.Kou,
J.G.Yonchuk,
H.G.Feldser,
Y.Sanchez,
J.P.Foley,
B.J.Bolognese,
G.Logan,
P.L.Podolin,
H.Yan,
J.F.Callahan,
T.D.Heightman,
J.K.Kerns.
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ABSTRACT
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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.
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