Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα

Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and NCoR1,2, which in turn recruit histone deacetylases to the chromatin(3-5). Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome (6-8). The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists(9). Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn alpha-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.