Molecular tuning of farnesoid X receptor partial agonism

The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an extended helix alpha 11 and the alpha 11-alpha 12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix alpha 12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix all that destabilizes the alpha 11-alpha 12 loop, a critical determinant for helix alpha 12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.