A structural mechanism of nuclear receptor biased agonism.

Abstract

TZDs are an FDA-approved class of anti-diabetes drugs that target the nuclear receptor PPARγ. These effective insulin sensitization drugs are marred by side effects that can lead to worse outcomes in patients. Efforts to develop non-TZD moiety PPARγ ligands are promising, though the way they create distinct signaling through PPARγ is not known. Here, we should note that some ligands cause PPARγ to bind transcriptomic coregulator proteins to different extents, favoring some over others (which we term “biased agonists”). Through novel crystal structures, fluorescence anisotropy affinity experiments, and isothermal calorimetry, we demonstrate that this bias is dependent on the type of structural cap or “anchor” in the coregulator that resides N-terminal to the LXXLL nuclear receptor-binding motif. This cap controls how the coregulator interacts with the nuclear receptor PPARγ; namely, whether and how the coregulator binds to the helix 4 of PPARγ. These capping motifs and their importance are rigorously defined here by crystal structure. Particularly thrilling is that the structural groups of coregulator interaction motifs defined here apply to almost all proteins in the nuclear receptor family due to their conserved structure on helix 4. These data illuminate how genes can be selectively controlled by ligands through nuclear receptors, and will inform the design of pharmaceutical drugs with fewer side effects.