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References listed in PDB file
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Key reference
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Title
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Crystal structure of the peroxisome proliferator-Activated receptor gamma (ppargamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.
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Authors
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R.Montanari,
F.Saccoccia,
E.Scotti,
M.Crestani,
C.Godio,
F.Gilardi,
F.Loiodice,
G.Fracchiolla,
A.Laghezza,
P.Tortorella,
A.Lavecchia,
E.Novellino,
F.Mazza,
M.Aschi,
G.Pochetti.
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Ref.
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J Med Chem, 2008,
51,
7768-7776.
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PubMed id
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Abstract
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The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent
transcription factors regulating glucose and lipid metabolism. The search for
new PPAR ligands with reduced adverse effects with respect to the marketed
antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is
highly desired. We report the crystal structure and activity of the two
enantiomeric forms of a clofibric acid analogue, respectively complexed with the
ligand-binding domain (LBD) of PPARgamma, and provide an explanation on a
molecular basis for their different potency and efficacy against PPARgamma. The
more potent S-enantiomer is a dual PPARalpha/PPARgamma agonist which presents a
partial agonism profile against PPARgamma. Docking of the S-enantiomer in the
PPARalpha-LBD has been performed to explain its different subtype
pharmacological profile. The hypothesis that partial agonists show differential
stabilization of helix 3, when compared to full agonists, is also discussed.
Moreover, the structure of the complex with the S-enantiomer reveals a new
region of the PPARgamma-LBD never sampled before by other ligands.
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Secondary reference #1
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Title
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Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-Activated receptor gamma ligand-Binding domain in the complex with two enantiomeric ligands.
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Authors
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G.Pochetti,
C.Godio,
N.Mitro,
D.Caruso,
A.Galmozzi,
S.Scurati,
F.Loiodice,
G.Fracchiolla,
P.Tortorella,
A.Laghezza,
A.Lavecchia,
E.Novellino,
F.Mazza,
M.Crestani.
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Ref.
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J Biol Chem, 2007,
282,
17314-17324.
[DOI no: ]
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PubMed id
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Figure 7.
FIGURE 7. C^  superposition of the
complexes with the R- and the S-enantiomer (in yellow and cyan,
respectively). Protein side chains of the complex with the
R-enantiomer are shown in green; the correspondent side-chains
are in pink for the complex with the S-enantiomer.
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Figure 11.
FIGURE 11. Superposition of the C^ traces of the complexes
of PPAR  with the R-enantiomer
(green), the S-enantiomer (cyan), and rosiglitazone (purple).
Putative contacts are shown in parentheses.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #2
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Title
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Partial agonists activate ppargamma using a helix 12 independent mechanism.
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Authors
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J.B.Bruning,
M.J.Chalmers,
S.Prasad,
S.A.Busby,
T.M.Kamenecka,
Y.He,
K.W.Nettles,
P.R.Griffin.
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Ref.
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Structure, 2007,
15,
1258-1271.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2. Overall Structure Comparison of PPARγ Bound to
Agonists and Partial Agonists
(A) Ribbon diagram of PPARγ
(green) bound to MRL-20 (yellow sticks).
(B) The figure
shows a Cα trace of superimposed PPARγ monomers bound to
rosiglitazone, MRL-20, MRL-24, nTZDpa, SR145, SR147, and BVT.13
Ligand-bound proteins colored as: rosiglitazone (PDB code: 2PRG)
(Nolte et al., 1998) (purple), MRL-20 (forest green), MRL-24
(pink), nTZDpa (green), SR145 (cyan), SR147 (orange), and BVT.13
(yellow). Ligands are not shown.
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Figure 7.
Figure 7. Structural Details of Hydrogen-Bonding Networks of
Full and Partial Agonists
PPARγ (green), rosiglitazone
(blue), MRL-20 (white), MRL-24 (yellow), nTZDpa (yellow), and
BVT.13 (white).
(A) Hydrogen-bonding network of the
rosiglitazone (PDB code: 2PRG) TZD head group to conserved
PPARγ residues (Nolte et al., 1998).
(B) Hydrogen-bonding
network of the MRL-20 lactate group to conserved PPARγ
residues.
(C) MRL-20 and MRL-24 represented as stick
figures as they lie in the binding pocket generated by
superimposition of the respective protein molecules.
(D)
The lactate group of MRL-24 contacts the β sheet making several
hydrogen bonds.
(E) The hydrogen bonding network of nTZDpa
contacts the β sheet and Arg288 adopts two defined
conformations.
(F) The hydrogen bonding network of BVT.13
contacts the β sheet.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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Secondary reference #3
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Title
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Asymmetry in the ppargamma/rxralpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
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Authors
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R.T.Gampe,
V.G.Montana,
M.H.Lambert,
A.B.Miller,
R.K.Bledsoe,
M.V.Milburn,
S.A.Kliewer,
T.M.Willson,
H.E.Xu.
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Ref.
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Mol Cell, 2000,
5,
545-555.
[DOI no: ]
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PubMed id
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Figure 4.
Figure 4. Recognition of 9cRA by RXRα(a) Ribbon drawings
of the RXRα LBD bound to the SRC-1 LxxLL motif (magenta) and
9cRA. The AF-2 helix (red) and residues surrounding the
conserved H3 lysine, which comprise the charge clamp, are
indicated.(b) Electron density map for 9cRA molecules. The map
was calculated in the absence of the compound with 2Fo-Fc
coefficients and contoured at 1.0 σ. The 9cRA carbons are shown
in green.(c) Interactions between 9cRA and RXRα. Residues
involved in hydrogen bond interactions and hydrophobic
interactions are indicated in blue and white, respectively.(d)
Docking conformation of 9cRA (green carbon atoms) in the RXRα
ligand-binding pocket (gray surface). atRA (purple carbon atoms)
from the atRA/RARγ structure is superimposed on the 9cRA/RXRα
structure.
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Figure 6.
Figure 6. Structure-Based Sequence Alignment of
Representative Nuclear ReceptorsOnly the regions that are
involved in the dimerization interface are shown. The PPARγ
residues that contact RXR are highlighted in yellow, and the
RXRα residues that contact PPARγ are highlighted in orange.
The secondary structures are noted under the sequences. The φ
ψKψψ ψKψψ Σ ψRψψ motif corresponds to the H10
sequences of F AKLL QKMT D LRQI in PPARγ and F AKLL LRLP A LRSI
in RXRα. Residues in HNF4, COUPTF1, ERα, and PR that diverge
significantly from the consensus motif are boxed. All residues
are colored according to their side chain properties (green for
hydrophobic, blue for positively charged, red for negatively
charged, and brown for polar). Dashes represent gaps in the
alignment.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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