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PDBsum entry 2rfd
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References listed in PDB file
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Key reference
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Title
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Inhibition of the egf receptor by binding of mig6 to an activating kinase domain interface.
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Authors
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X.Zhang,
K.A.Pickin,
R.Bose,
N.Jura,
P.A.Cole,
J.Kuriyan.
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Ref.
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Nature, 2007,
450,
741-744.
[DOI no: ]
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PubMed id
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Abstract
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Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2,
ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy.
Critical for activation is the formation of an asymmetric dimer by the
intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one
kinase domain induces an active conformation in the other. The cytoplasmic
protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and
inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of
complexes between the EGFR kinase domain and a fragment of MIG6 show that a
approximately 25-residue epitope (segment 1) from MIG6 binds to the distal
surface of the C lobe of the kinase domain. Biochemical and cell-based analyses
confirm that this interaction contributes to EGFR inhibition by blocking the
formation of the activating dimer interface. A longer MIG6 peptide that is
extended C terminal to segment 1 has increased potency as an inhibitor of the
activated EGFR kinase domain, while retaining a critical dependence on segment
1. We show that signalling by EGFR molecules that contain constitutively active
kinase domains still requires formation of the asymmetric dimer, underscoring
the importance of dimer interface blockage in MIG6-mediated inhibition.
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Figure 3.
Figure 3: Inhibition of EGFR kinase activity by MIG6(segments
1–2). a, Inhibition of the L834R mutant kinase in solution
by peptides 336–412 or 336–412(Y358A) (containing both
segment 1 and 2). The 30-residue peptide (containing segment 1
only) is used as a control. The insert shows an expanded view at
low peptide concentrations. b, Inhibition of the wild-type
kinase in solution by peptides 336–412 or 336–412(Y358A).
Titration of peptide 336–412 beyond 30  M
leads to unreliable results owing to precipitation of the
protein and peptide (see Methods).
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Figure 4.
Figure 4: A double-headed mechanism for EGFR inhibition by MIG6.
a, A co-transfection experiment showing that EGFR(activator)
can activate EGFR(activatable), and that MIG6 can inhibit this
activation. b, Co-transfection experiments showing that
full-length EGFR containing the L834R/V924R double mutation only
shows autophosphorylation when co-transfected with
EGFR(activator). Co-transfection combinations in a and b are
represented by the cartoons in the respective lower panels, for
clarity. The I682Q, D813N, L834R and V924R mutations are denoted
in the cartoons by a circle, diamond, star and triangle,
respectively. c, A schematic diagram showing the double-headed
mechanism for EGFR inhibition by MIG6 involving both segment 1
and segment 2.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2007,
450,
741-744)
copyright 2007.
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