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PDBsum entry 2gpu
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Transcription
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PDB id
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2gpu
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References listed in PDB file
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Key reference
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Title
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X-Ray crystal structures of the estrogen-Related receptor-Gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation.
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Authors
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L.Wang,
W.J.Zuercher,
T.G.Consler,
M.H.Lambert,
A.B.Miller,
L.A.Orband-Miller,
D.D.Mckee,
T.M.Willson,
R.T.Nolte.
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Ref.
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J Biol Chem, 2006,
281,
37773-37781.
[DOI no: ]
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PubMed id
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Abstract
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X-ray crystal structures of the ligand binding domain (LBD) of the
estrogen-related receptor-gamma (ERRgamma) were determined that describe this
receptor in three distinct states: unliganded, inverse agonist bound, and
agonist bound. Two structures were solved for the unliganded state, the ERRgamma
LBD alone, and in complex with a coregulator peptide representing a portion of
receptor interacting protein 140 (RIP140). No significant differences were seen
between these structures that both exhibited the conformation of ERRgamma seen
in studies with other coactivators. Two structures were obtained describing the
inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT),
and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the
silencing mediator of retinoid and thyroid hormone action protein (SMRT). The
4-OHT structure was similar to other reported inverse agonist bound structures,
showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix
relative to the unliganded structures with little other rearrangement occurring.
No significant changes to the LBD appear to be induced by peptide binding with
the addition of the SMRT peptide to the ERRgamma plus 4-OHT complex. The
observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and
the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding
residues. Thermal stability studies show that agonist binding leads to global
stabilization of the ligand binding domain. In contrast to the conventional
mechanism of nuclear receptor ligand activation, activation of ERRgamma by
GSK4716 does not appear to involve a major rearrangement or significant
stabilization of the C-terminal helix.
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Figure 4.
FIGURE 4. ERR  ·4-OHT·SMRT
complex. The tetrameric assembly containing four of the six
molecules in the asymmetric unit is shown. A ribbon
representation of the ERR monomers is shown with
each monomer shown with a distinct color: yellow, molecule A;
magenta, molecule B; blue, molecule C; and green, molecule D.
The ligand is depicted as a stick figure with orange carbon
atoms. Residues 319-330 of the SMRT peptide are depicted as cyan
ribbons with peptide chain G binding ERR chain A and peptide
chain H binding ERR chain B. The remaining
two molecules in the asymmetric unit form a similar tetramer
with symmetrically related copies of themselves around a
crystallographic 2-fold axis.
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Figure 7.
FIGURE 7. Plot of ligand interactions in the ERR ·GSK4716·RIP140
complex. Hydrogen bonds involving the ligand are shown in red,
with distances denoted in angstroms. The ligand hydrogen bonds
directly to two residues, the side chain of Asp-328 and the back
bone carbonyl of Tyr-327. Indirect hydrogen bonds to the ligand
exist through two waters to the side chain of Arg-316 and the
main chain of Leu-309. Residues denoted in blue are >4.0 Å
from the ligand.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
37773-37781)
copyright 2006.
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