1. Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA

Correspondence to: H. Eric Xu Correspondence and requests for materials should be addressed to H.E.X. (e-mail: Email: ex11957@gsk.com). The Protein Data Bank code for the PPAR/GW6471/SMRT complex and the PPAR/GW409544/SRC-1 complex is 1KQQ and 1K7L, respectively.

Abstract

Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR^{1, 2}, which in turn recruit histone deacetylases to the chromatin^{3, 4, 5}. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome^{6, 7, 8}. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists⁹. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor- 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 -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.