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PDBsum entry 2p1v
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Hormone receptor
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PDB id
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2p1v
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References listed in PDB file
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Key reference
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Title
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Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function.
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Authors
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V.Nahoum,
E.Pérez,
P.Germain,
F.Rodríguez-Barrios,
F.Manzo,
S.Kammerer,
G.Lemaire,
O.Hirsch,
C.A.Royer,
H.Gronemeyer,
A.R.De lera,
W.Bourguet.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
17323-17328.
[DOI no: ]
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PubMed id
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Abstract
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Retinoid X receptors (RXRalpha, -beta, and -gamma) occupy a central position in
the nuclear receptor superfamily, because they form heterodimers with many other
family members and hence are involved in the control of a variety of
(patho)physiologic processes. Selective RXR ligands, referred to as rexinoids,
are already used or are being developed for cancer therapy and have promise for
the treatment of metabolic diseases. However, important side effects remain
associated with existing rexinoids. Here we describe the rational design and
functional characterization of a spectrum of RXR modulators ranging from partial
to pure antagonists and demonstrate their utility as tools to probe the
implication of RXRs in cell biological phenomena. One of these ligands renders
RXR activity particularly sensitive to coactivator levels and has the potential
to act as a cell-specific RXR modulator. A combination of crystallographic and
fluorescence anisotropy studies reveals the molecular details accounting for the
agonist-to-antagonist transition and provides direct experimental evidence for a
correlation between the pharmacological activity of a ligand and its impact on
the structural dynamics of the activation helix H12. Using RXR and its cognate
ligands as a model system, our correlative analysis of 3D structures and dynamic
data provides an original view on ligand actions and enables the establishment
of mechanistic concepts, which will aid in the development of selective nuclear
receptor modulators.
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Figure 1.
Fig. 1. Structures of the agonist CD3254 (compound 1) and
of the series of alkyl ether analogs 2a–f.
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Figure 4.
Fig. 4. Structures of RXR  LBD in complex with
partial agonists. (A) Overall structure of RXR LBD in
complex with 2a, 2b, or 2c. The ligand is represented by red
(oxygen atoms) and yellow (carbon atoms) van der Waals spheres.
Helices and  -strands are numbered
from N to C terminus. Together, helices H3, H4, and H12 define
the activation function 2 (AF-2) surface to which the TIF2 NR2
peptide is bound. (B) 2F[o]–F[c] density (1  ) for
the LBP of RXR bound to 2b. W
indicates a water molecule. (C) Closeup view showing the
hydrogen bond network that stabilizes a water molecule in close
proximity of L436. An identical hydrogen bond network is
observed in the complex with 2a (not shown). (D) Superposition
of the RXR LBP with 2b and 2c. (E) Comparison with the structure
of RXR LBD bound to SR11237
(Protein Data Bank ID code 1MVC). To accommodate the particular
features of 2a–c, L436 must adopt a conformation that differs
from that found in the presence of the agonist. The dashed line
between L436 and L455 indicates a short distance.
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