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PDBsum entry 4jdd
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Signaling protein/peptide
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PDB id
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4jdd
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References listed in PDB file
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Key reference
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Title
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Interaction of 14-3-3 proteins with the estrogen receptor alpha f domain provides a drug target interface.
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Authors
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I.J.De vries-Van leeuwen,
D.Da costa pereira,
K.D.Flach,
S.R.Piersma,
C.Haase,
D.Bier,
Z.Yalcin,
R.Michalides,
K.A.Feenstra,
C.R.Jiménez,
T.F.De greef,
L.Brunsveld,
C.Ottmann,
W.Zwart,
A.H.De boer.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
8894-8899.
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PubMed id
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Abstract
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Estrogen receptor alpha (ERα) is involved in numerous physiological and
pathological processes, including breast cancer. Breast cancer therapy is
therefore currently directed at inhibiting the transcriptional potency of ERα,
either by blocking estrogen production through aromatase inhibitors or
antiestrogens that compete for hormone binding. Due to resistance, new treatment
modalities are needed and as ERα dimerization is essential for its activity,
interference with receptor dimerization offers a new opportunity to exploit in
drug design. Here we describe a unique mechanism of how ERα dimerization is
negatively controlled by interaction with 14-3-3 proteins at the extreme C
terminus of the receptor. Moreover, the small-molecule fusicoccin (FC)
stabilizes this ERα/14-3-3 interaction. Cocrystallization of the trimeric
ERα/14-3-3/FC complex provides the structural basis for this stabilization and
shows the importance of phosphorylation of the penultimate Threonine
(ERα-T(594)) for high-affinity interaction. We confirm that T(594) is a
distinct ERα phosphorylation site in the breast cancer cell line MCF-7 using a
phospho-T(594)-specific antibody and by mass spectrometry. In line with its
ERα/14-3-3 interaction stabilizing effect, fusicoccin reduces the
estradiol-stimulated ERα dimerization, inhibits ERα/chromatin interactions and
downstream gene expression, resulting in decreased cell proliferation. Herewith,
a unique functional phosphosite and an alternative regulation mechanism of ERα
are provided, together with a small molecule that selectively targets this
ERα/14-3-3 interface.
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