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PDBsum entry 4znh
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Transcription
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PDB id
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4znh
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References listed in PDB file
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Key reference
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Title
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Predictive features of ligand-Specific signaling through the estrogen receptor.
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Authors
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J.C.Nwachukwu,
S.Srinivasan,
Y.Zheng,
S.Wang,
J.Min,
C.Dong,
Z.Liao,
J.Nowak,
N.J.Wright,
R.Houtman,
K.E.Carlson,
J.S.Josan,
O.Elemento,
J.A.Katzenellenbogen,
H.B.Zhou,
K.W.Nettles.
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Ref.
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Mol Syst Biol, 2016,
12,
864.
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PubMed id
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Abstract
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Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as
tamoxifen have tissue-selective or cell-specific activities, while others have
similar activities in different cell types. To identify biophysical determinants
of cell-specific signaling and breast cancer cell proliferation, we synthesized
241 ERα ligands based on 19 chemical scaffolds, and compared ligand response
using quantitative bioassays for canonical ERα activities and X-ray
crystallography. Ligands that regulate the dynamics and stability of the
coactivator-binding site in the C-terminal ligand-binding domain, called
activation function-2 (AF-2), showed similar activity profiles in different cell
types. Such ligands induced breast cancer cell proliferation in a manner that
was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and
induction of the GREB1 proliferative gene. For some ligand series, a single
inter-atomic distance in the ligand-binding domain predicted their proliferative
effects. In contrast, the N-terminal coactivator-binding site, activation
function-1 (AF-1), determined cell-specific signaling induced by ligands that
used alternate mechanisms to control cell proliferation. Thus, incorporating
systems structural analyses with quantitative chemical biology reveals how
ligands can achieve distinct allosteric signaling outcomes through ERα.
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