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PDBsum entry 1xap
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Transcription
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PDB id
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1xap
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References listed in PDB file
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Key reference
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Title
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Rational design of rar-Selective ligands revealed by rarbeta crystal stucture.
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Authors
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P.Germain,
S.Kammerer,
E.Pérez,
C.Peluso-Iltis,
D.Tortolani,
F.C.Zusi,
J.Starrett,
P.Lapointe,
J.P.Daris,
A.Marinier,
A.R.De lera,
N.Rochel,
H.Gronemeyer.
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Ref.
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EMBO Rep, 2004,
5,
877-882.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour
suppressor, reveals important features that distinguish it from the two other
RAR isotypes. The most striking difference is an extra cavity allowing RARbeta
to bind more bulky agonists. Accordingly, we identified a ligand that shows
RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or
gamma isotypes. The structural differences between the three RAR ligand-binding
pockets revealed a rationale explaining how a single retinoid can be at the same
time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we
demonstrate how to generate an RARbeta antagonist by gradually modifying the
bulkiness of a single substitution. Together, our results provide structural
guidelines for the synthesis of RARbeta-selective agonists and antagonists,
allowing for the first time to address pharmacologically the tumour suppressor
role of RARbeta in vitro and in animal models.
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Figure 1.
Figure 1 Crystal structure of the RAR  LBD
-TTNPB complex reveals an additional cavity in the RAR LBP.
(A) Electron density map of TTNPB in its pocket. 2F[o] -F[c] map
at 2.1 Å resolution contoured at 1  .
The three isotype-specific residues (A[225], I[263] and V[388])
and residues anchoring the carboxylate (R[269] and S[280]) are
indicated. Illustration by PYMOL. (B) Superposition of the
holo-RAR -TTNPB
(yellow) and RAR  -9-cis
RA (blue) LBDs. Illustration by SETOR. (C) Superposition of
TTNPB -RAR (blue)
and 9-cis RA -RAR (grey)
LBDs. The isotype-specific residues are shown in cyan (RAR )
and orange (RAR )
and TTNPB in yellow. The carboxylate anchoring residues are
illustrated as ball-and-sticks. H bonds are represented as
dashed lines. The figure was prepared by MOLSCRIPT and RASTER3D.
(D) Superimposition of RAR (blue)
and RAR (grey)
LBPs. The arrow points to the additional cavity in RAR .
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Figure 5.
Figure 5 The three divergent LBP residues determine the RAR selectivity
of BMS641 and the isotype-dependent potential of BMS453. (A)
Partial proteolysis maps of in vitro-translated RARs in the
presence or absence of increasing concentrations of either
TTNPB, BMS453 or BMS641, as indicated. (B) Dose -response curves
to assess the binding affinity of BMS641 relative to TTNPB in
RAR pocket mutants. HeLa cells were co-transfected with
(RARE)3x-tk-luc and either RAR (closed
triangles), RAR (open
circles), RAR  arrow
(RAR
(M[272]I,
A[397]V); open squares) or RAR arrow
(RAR
(I[263]M,
V[388]A); closed diamonds) and reporter gene transcription was
induced with 3 nM TTNPB (100%). (C) BMS453-induced luciferase
activity in HeLa cells co-transfected with (RARE)3x-tk-luc and
the indicated receptors.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO Rep
(2004,
5,
877-882)
copyright 2004.
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