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PDBsum entry 1x2j
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Transcription
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PDB id
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1x2j
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References listed in PDB file
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Key reference
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Title
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Structural basis for defects of keap1 activity provoked by its point mutations in lung cancer.
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Authors
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B.Padmanabhan,
K.I.Tong,
T.Ohta,
Y.Nakamura,
M.Scharlock,
M.Ohtsuji,
M.I.Kang,
A.Kobayashi,
S.Yokoyama,
M.Yamamoto.
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Ref.
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Mol Cell, 2006,
21,
689-700.
[DOI no: ]
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PubMed id
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Abstract
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Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses
Nrf2 through its molecular interaction. To elucidate the molecular mechanism of
the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller
crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed
that extensive inter- and intrablade hydrogen bonds maintain the structural
integrity and proper association of Keap1 with Nrf2. A peptide containing the
ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the
central cavity on the bottom side via electrostatic interactions with conserved
arginine residues. We found a somatic mutation and a gene variation in human
lung cancer cells that change glycine to cysteine in the DGR domain, introducing
local conformational changes that reduce Keap1's affinity for Nrf2. These
results provide a structural basis for the loss of Keap1 function and gain of
Nrf2 function.
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Figure 5.
Figure 5. Somatic Mutation (G430C) and Gene Variation
(G364C) in Keap1 Hamper Repression Activity of Keap1 on Nrf2
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Figure 7.
Figure 7. G364C and G430C Mutations Lead to Disruptions of
the Intermolecular Interactions
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2006,
21,
689-700)
copyright 2006.
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