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PDBsum entry 4cxj
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Transcription
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PDB id
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4cxj
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PDB id:
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| Name: |
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Transcription
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Title:
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Btb domain of keap1 c151w mutant
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Structure:
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Kelch-like ech-associated protein 1. Chain: a. Fragment: btb domain, residues 48-180. Synonym: cytosolic inhibitor of nrf2, inrf2, kelch-like protein 19, keap1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.80Å
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R-factor:
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0.215
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R-free:
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0.271
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Authors:
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A.Cleasby,J.Yon,P.J.Day,C.Richardson,I.J.Tickle,P.A.Williams, J.F.Callahan,R.Carr,N.Concha,J.K.Kerns,H.Qi,T.Sweitzer,P.Ward, T.G.Davies
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Key ref:
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A.Cleasby
et al.
(2014).
Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO.
Plos One,
9,
e98896.
PubMed id:
DOI:
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Date:
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07-Apr-14
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Release date:
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18-Jun-14
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PROCHECK
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Headers
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References
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Q14145
(KEAP1_HUMAN) -
Kelch-like ECH-associated protein 1 from Homo sapiens
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Seq:
Struc:
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624 a.a.
131 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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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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DOI no:
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Plos One
9:e98896
(2014)
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PubMed id:
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Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO.
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A.Cleasby,
J.Yon,
P.J.Day,
C.Richardson,
I.J.Tickle,
P.A.Williams,
J.F.Callahan,
R.Carr,
N.Concha,
J.K.Kerns,
H.Qi,
T.Sweitzer,
P.Ward,
T.G.Davies.
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ABSTRACT
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The protein Keap1 is central to the regulation of the Nrf2-mediated
cytoprotective response, and is increasingly recognized as an important target
for therapeutic intervention in a range of diseases involving excessive
oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in
sensing environmental electrophiles and in mediating interactions with the
Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for
several small molecule covalent activators of the Nrf2 pathway. However, despite
structural information being available for several BTB domains from related
proteins, there have been no reported crystal structures of Keap1 BTB, and this
has precluded a detailed understanding of its mechanism of action and
interaction with antagonists. We report here the first structure of the BTB
domain of Keap1, which is thought to contain the key cysteine residue
responsible for interaction with electrophiles, as well as structures of the
covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively
inactive C151W BTB mutant. In addition to providing the first structural
confirmation of antagonist binding to Keap1 BTB, we also present biochemical
evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding
of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2
activation through disruption of the BTB-Cul3 interface.
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Links
