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PDBsum entry 2qa8
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Transcription
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PDB id
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2qa8
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References listed in PDB file
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Key reference
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Title
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Nfkappab selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses.
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Authors
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K.W.Nettles,
J.B.Bruning,
G.Gil,
J.Nowak,
S.K.Sharma,
J.B.Hahm,
K.Kulp,
R.B.Hochberg,
H.Zhou,
J.A.Katzenellenbogen,
B.S.Katzenellenbogen,
Y.Kim,
A.Joachmiak,
G.L.Greene.
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Ref.
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Nat Chem Biol, 2008,
4,
241-247.
[DOI no: ]
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PubMed id
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Abstract
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Our understanding of how steroid hormones regulate physiological functions has
been significantly advanced by structural biology approaches. However, progress
has been hampered by misfolding of the ligand binding domains in heterologous
expression systems and by conformational flexibility that interferes with
crystallization. Here, we show that protein folding problems that are common to
steroid hormone receptors are circumvented by mutations that stabilize
well-characterized conformations of the receptor. We use this approach to
present the structure of an apo steroid receptor that reveals a
ligand-accessible channel allowing soaking of preformed crystals. Furthermore,
crystallization of different pharmacological classes of compounds allowed us to
define the structural basis of NFkappaB-selective signaling through the estrogen
receptor, thus revealing a unique conformation of the receptor that allows
selective suppression of inflammatory gene expression. The ability to
crystallize many receptor-ligand complexes with distinct pharmacophores allows
one to define structural features of signaling specificity that would not be
apparent in a single structure.
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Figure 2.
(a) Shown is the structure of tamoxifen-bound ER  (PDB
code 3ERT) as a ribbon diagram. Helices 3–5 are colored pink,
and helix 12 is colored red. (b) Molecular modeling suggests
that the mutation L536S of ER promotes
a stabilizing interaction between helix 12 and Glu380 in helix 3.
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Figure 3.
(a) The structure of genistein-bound ER Y537S
is depicted as a ribbon diagram, showing only a portion of the
molecule that interacts with the ligand. The closed interface
between helix 11 and L7-8 is shown by a red circle.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2008,
4,
241-247)
copyright 2008.
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