Molecular recognition of fatty acids by peroxisome proliferator-activated receptors

The peroxisome proliferator-activated receptors (PPARs) are nuclear recepto rs for fatty acids (FAs) that regulate glucose and lipid homeostasis. We re port the crystal structure of the PPAR delta ligand-binding domain (LBD) bo und to either the FA eicosapentaenoic acid (EPA) or the synthetic fibrate G W2433. The carboxylic acids of EPA and GW2433 interact directly with the ac tivation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two di stinct conformations within the large hydrophobic cavity. GW2433 occupies e ssentially the same space as EPA bound in both conformations. These structu res provide molecular insight into the propensity for PPARs to interact wit h a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.