Molecular tuning of farnesoid X receptor partial agonism

Nat Commun. 2019 Jul 2;10(1):2915. doi: 10.1038/s41467-019-10853-2.

Abstract

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 α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix α11 that destabilizes the α11-α12 loop, a critical determinant for helix α12 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Liver / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Co-Repressor Proteins
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor