Xu H E, Lambert M H, Montana V G, Parks D J, Blanchard S G, Brown P J, Sternbach D D, Lehmann J M, Wisely G B, Willson T M, Kliewer S A, Milburn M V
Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Mol Cell. 1999 Mar;3(3):397-403. doi: 10.1016/s1097-2765(00)80467-0.
The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPAR delta ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fibrate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation.
过氧化物酶体增殖物激活受体（PPARs）是脂肪酸（FAs）的核受体，可调节葡萄糖和脂质稳态。我们报道了与脂肪酸二十碳五烯酸（EPA）或合成贝特类药物GW2433结合的PPARδ配体结合域（LBD）的晶体结构。EPA和GW2433的羧酸直接与激活功能2（AF-2）螺旋相互作用。EPA的疏水尾部在大疏水腔内采取两种不同的构象。GW2433在两种构象中占据的空间与结合的EPA基本相同。这些结构为PPARs与各种合成和天然化合物相互作用的倾向提供了分子层面的见解，这些化合物包括链长度和饱和度都不同的脂肪酸。
