Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor γ to PGC-1α

The functional interaction between the peroxisome proliferator-activated receptor gamma (PPAR gamma) and its coactivator PGC-1 alpha is crucial for the normal physiology of PPAR gamma and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR gamma ligand-binding domain bound to rosiglitazone and to a large PGC-1 alpha fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1 alpha and the PPAR gamma coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1 alpha is capable of binding to PPAR gamma. Our studies reveal that the strong interaction of PGC-1 alpha and PPAR gamma is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1 alpha indicate that the first PGC-1 alpha motif is necessary and sufficient for PGC-1 alpha to coactivate PPAR gamma in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR gamma and PGC-1 alpha in glucose homeostasis and adipocyte differentiation.