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PDBsum entry 4l96
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Transcription/transcription inhibitor
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PDB id
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4l96
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References listed in PDB file
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Key reference
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Title
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Structural basis of the transactivation deficiency of the human pparγ f360l mutant associated with familial partial lipodystrophy.
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Authors
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C.Lori,
A.Pasquo,
R.Montanari,
D.Capelli,
V.Consalvi,
R.Chiaraluce,
L.Cervoni,
F.Loiodice,
A.Laghezza,
M.Aschi,
A.Giorgi,
G.Pochetti.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2014,
70,
1965-1976.
[DOI no: ]
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PubMed id
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Abstract
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The peroxisome proliferator-activated receptors (PPARs) are transcription
factors that regulate glucose and lipid metabolism. The role of PPARs in several
chronic diseases such as type 2 diabetes, obesity and atherosclerosis is well
known and, for this reason, they are the targets of antidiabetic and
hypolipidaemic drugs. In the last decade, some rare mutations in human PPARγ
that might be associated with partial lipodystrophy, dyslipidaemia, insulin
resistance and colon cancer have emerged. In particular, the F360L mutant of
PPARγ (PPARγ2 residue 388), which is associated with familial partial
lipodystrophy, significantly decreases basal transcriptional activity and
impairs stimulation by synthetic ligands. To date, the structural reason for
this defective behaviour is unclear. Therefore, the crystal structure of PPARγ
F360L together with the partial agonist LT175 has been solved and the mutant has
been characterized by circular-dichroism spectroscopy (CD) in order to compare
its thermal stability with that of the wild-type receptor. The X-ray analysis
showed that the mutation induces dramatic conformational changes in the
C-terminal part of the receptor ligand-binding domain (LBD) owing to the loss of
van der Waals interactions made by the Phe360 residue in the wild type and an
important salt bridge made by Arg357, with consequent rearrangement of loop
11/12 and the activation function helix 12 (H12). The increased mobility of H12
makes the binding of co-activators in the hydrophobic cleft less efficient,
thereby markedly lowering the transactivation activity. The spectroscopic
analysis in solution and molecular-dynamics (MD) simulations provided results
which were in agreement and consistent with the mutant conformational changes
observed by X-ray analysis. Moreover, to evaluate the importance of the salt
bridge made by Arg357, the crystal structure of the PPARγ R357A mutant in
complex with the agonist rosiglitazone has been solved.
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Secondary reference #1
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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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