Molecular tuning of farnesoid X receptor partial agonism

• DOI: 10.1038/s41467-019-10853-2
• Publication Date: 2019-07-02T10:02:56Z
• Authors: Daniel Merk; Sridhar Sreeramulu; Denis Kudlinzki; Krishna Saxena; Verena Linhard; Santosh L. Gande; Fabian Hiller; Christina Lamers; Ewa Nilsson; Anna Aagaard; Lisa Wissler; Niek Dekker; Krister Bamberg; Manfred Schubert-...; Harald Schwalbe
• Keywords: Male; Protein Conformation, alpha-Helical; 0301 basic medicine; Magnetic Resonance Spectroscopy; Science; Q; Receptors, Cytoplasmic and Nuclear; Hydrogen Bonding; Ligands; Article; Cell Line; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Animals; Humans; Co-Repressor Proteins; Protein Binding

AbstractThe 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.