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PDBsum entry 3cdp
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Transcription
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PDB id
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3cdp
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References listed in PDB file
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Key reference
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Title
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Synthesis, Biological evaluation and molecular investigation of fluorinated peroxisome proliferator-Activated receptors α/γ dual agonists.
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Authors
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G.Fracchiolla,
A.Laghezza,
L.Piemontese,
M.Parente,
A.Lavecchia,
G.Pochetti,
R.Montanari,
C.Di giovanni,
G.Carbonara,
P.Tortorella,
E.Novellino,
F.Loiodice.
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Ref.
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Bioorg Med Chem Lett, 2012,
20,
2141-2151.
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PubMed id
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Abstract
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PPARs are transcription factors that govern lipid and glucose homeostasis and
play a central role in cardiovascular disease, obesity, and diabetes. Thus,
there is significant interest in developing new agonists for these receptors.
Given that the introduction of fluorine generally has a profound effect on the
physical and/or biological properties of the target molecule, we synthesized a
series of fluorinated analogs of the previously reported compound 2, some of
which turned out to be remarkable PPARα and PPARγ dual agonists. Docking
experiments were also carried out to gain insight into the interactions of the
most active derivatives with both receptors.
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Secondary reference #1
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Title
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Structural determinants of ligand binding selectivity between the peroxisome proliferator-Activated receptors.
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Authors
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H.E.Xu,
M.H.Lambert,
V.G.Montana,
K.D.Plunket,
L.B.Moore,
J.L.Collins,
J.A.Oplinger,
S.A.Kliewer,
R.T.Gampe,
D.D.Mckee,
J.T.Moore,
T.M.Willson.
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Ref.
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Proc Natl Acad Sci U S A, 2001,
98,
13919-13924.
[DOI no: ]
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PubMed id
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Figure 2.
Fig. 2. X-ray crystal structure of the PPAR  LBD. (A)
The PPAR protein is
displayed as a red worm with the AF2 helix in red and K292 in
dark blue. The LxxLL peptide is displayed as a purple worm. The
agonist ligand GW409544 is displayed in space-filling
representation colored by atom type. The solvent-accessible
ligand binding pocket is shown as a white dot surface. Helices
2, 2', 3, 9, and 10 are indicated. The amino acids Phe-273,
Lys-292, Tyr-314, Glu-462, and Tyr-464 are displayed in light
blue. (B) A 2F[o]  F[c] omit
map showing the electron density (1  ) of the
ligand and the surrounding residues. (C) Key hydrogen bonding
(yellow line) and hydrophobic (white broken line) interactions
between GW409544 and the PPAR protein and
a bound water molecule.
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Figure 3.
Fig. 3. X-ray crystal structure of the PPAR  /RXR LBDs. (A)
The PPAR protein is
displayed as a yellow worm and the RXR protein as
a dark blue worm with the LxxLL peptides in purple. The agonist
ligands GW409544 and 9-cis-retinoic acid are displayed in
space-filling representations colored by atom type. (B) A 2F[o]
F[c] omit
map showing the electron density (1 ) of the
ligand and the surrounding residues. The amino acids Phe-282,
Tyr-323, and Tyr-473 are indicated. (C) Key hydrogen bonding
(yellow line) and hydrophobic (white broken line) interactions
between GW409544 and the PPAR protein and
two bound water molecules.
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