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* Residue conservation analysis
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PDB id:
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Transcription
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Title:
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Crystal structure of the estrogen receptor alpha ligand binding domain mutant 537s complexed with genistein
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Structure:
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Estrogen receptor. Chain: a. Fragment: steroid-binding region, residues 298-554. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Mutation: yes. Estrogen receptor. Chain: b. Fragment: steroid-binding region, residues 298-554.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, esr, nr3a1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Mus musculus. Mouse.
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Resolution:
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1.85Å
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R-factor:
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0.214
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R-free:
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0.264
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Authors:
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K.W.Nettles,J.B.Bruning,J.Nowak,S.K.Sharma,J.B.Hahm,Y.Shi,K.Kulp, R.B.Hochberg,H.Zhou,J.A.Katzenellenbogen,B.S.Katzenellenbogen,Y.Kim, A.Joachmiak,G.L.Greene
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Key ref:
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K.W.Nettles
et al.
(2008).
NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses.
Nat Chem Biol,
4,
241-247.
PubMed id:
DOI:
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Date:
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14-Jun-07
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Release date:
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18-Mar-08
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PROCHECK
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Headers
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References
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DOI no:
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Nat Chem Biol
4:241-247
(2008)
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PubMed id:
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NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses.
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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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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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Selected figure(s)
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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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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.le Maire,
W.Bourguet,
and
P.Balaguer
(2010).
A structural view of nuclear hormone receptor: endocrine disruptor interactions.
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Cell Mol Life Sci,
67,
1219-1237.
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PDB code:
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J.B.Bruning,
A.A.Parent,
G.Gil,
M.Zhao,
J.Nowak,
M.C.Pace,
C.L.Smith,
P.V.Afonine,
P.D.Adams,
J.A.Katzenellenbogen,
and
K.W.Nettles
(2010).
Coupling of receptor conformation and ligand orientation determine graded activity.
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Nat Chem Biol,
6,
837-843.
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PDB codes:
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S.H.Kim,
J.R.Gunther,
and
J.A.Katzenellenbogen
(2010).
Monitoring a coordinated exchange process in a four-component biological interaction system: development of a time-resolved terbium-based one-donor/three-acceptor multicolor FRET system.
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J Am Chem Soc,
132,
4685-4692.
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S.Möcklinghoff,
R.Rose,
M.Carraz,
A.Visser,
C.Ottmann,
and
L.Brunsveld
(2010).
Synthesis and crystal structure of a phosphorylated estrogen receptor ligand binding domain.
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Chembiochem,
11,
2251-2254.
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PDB codes:
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S.N.Giraud,
C.M.Caron,
D.Pham-Dinh,
P.Kitabgi,
and
A.B.Nicot
(2010).
Estradiol inhibits ongoing autoimmune neuroinflammation and NFkappaB-dependent CCL2 expression in reactive astrocytes.
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Proc Natl Acad Sci U S A,
107,
8416-8421.
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H.C.Raaijmakers,
J.E.Versteegh,
and
J.C.Uitdehaag
(2009).
The X-ray Structure of RU486 Bound to the Progesterone Receptor in a Destabilized Agonistic Conformation.
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J Biol Chem,
284,
19572-19579.
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PDB code:
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I.J.McEwan,
and
A.M.Nardulli
(2009).
Nuclear hormone receptor architecture - form and dynamics: The 2009 FASEB Summer Conference on Dynamic Structure of the Nuclear Hormone Receptors.
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Nucl Recept Signal,
7,
e011.
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S.H.Kim,
J.R.Gunther,
and
J.A.Katzenellenbogen
(2008).
Nonclassical SNAPFL analogue as a Cy5 resonance energy transfer partner.
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Org Lett,
10,
4931-4934.
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S.Mader
(2008).
Fast-tracking steroid receptor crystallization.
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Nat Chem Biol,
4,
226-227.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
