Ácidos graxos de cadeia média como ligantes da proteína PPAR [thesis]

Marcelo Vizoná Liberato
PPARs (peroxisome proliferator activated receptors) are nuclear receptors that regulate glucose and fat metabolism, adipogenesis and macrophage polarization and mediate actions of a major class of drugs that are used to treat type 2 diabetes, the thiazolidinediones. While TZDs reduce blood glucose and improve insulin sensitivity effectively, they can also exhibit deleterious side effects such as increased cardiovascular risk, weight gain, fluid retention and liver toxicity. Because it is
more » ... le to develop new PPARγ drugs with more favorable spectrums of response, mechanisms of PPARγ ligand activation have come under intense scrutiny. To understand relationships between PPARγ ligand binding and transcriptional activation, we sought to obtain apo human PPARγ-LBD (ligand binding domain) crystals that diffract to high resolution. More surprisingly, close analysis of the ligand binding pocket revealed the presence of three small molecules, identified as nonanoic acid and octanoic acid. Here, we report the X-ray structural analysis of the PPARγ LBD complexed with three bacterial (expression organism) medium chain fatty acids (MCFAs) that simultaneously occupy the buried ligand binding pocket (LBP). Structural and functional analysis suggests that MCFAs are partial agonists that stabilize PPARγ LBD conformation, through a helix 12 independent mechanism.
doi:10.11606/d.76.2009.tde-19032009-111236 fatcat:ir773c7ezvf3vkaiplsvuxnd3a