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PDBsum entry 3d6d
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Transcription
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PDB id
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3d6d
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Contents |
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* Residue conservation analysis
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J Med Chem
51:7768-7776
(2008)
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PubMed id:
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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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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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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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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.Gioiello,
A.Macchiarulo,
A.Carotti,
P.Filipponi,
G.Costantino,
G.Rizzo,
L.Adorini,
and
R.Pellicciari
(2011).
Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine.
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Bioorg Med Chem,
19,
2650-2658.
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B.O.Al-Najjar,
H.A.Wahab,
T.S.Tengku Muhammad,
A.C.Shu-Chien,
N.A.Ahmad Noruddin,
and
M.O.Taha
(2011).
Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.
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Eur J Med Chem,
46,
2513-2529.
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J.Fidelak,
S.Ferrer,
M.Oberlin,
D.Moras,
A.Dejaegere,
and
R.H.Stote
(2010).
Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein.
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Eur Biophys J,
39,
1503-1512.
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S.N.Lewis,
J.Bassaganya-Riera,
and
D.R.Bevan
(2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
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PPAR Res,
2010,
861238.
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T.Waku,
T.Shiraki,
T.Oyama,
K.Maebara,
R.Nakamori,
and
K.Morikawa
(2010).
The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites.
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EMBO J,
29,
3395-3407.
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PDB codes:
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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
codes are
shown on the right.
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Links
