1. Molecular tuning of farnesoid X receptor partial agonism.
- Author
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Merk D, Sreeramulu S, Kudlinzki D, Saxena K, Linhard V, Gande SL, Hiller F, Lamers C, Nilsson E, Aagaard A, Wissler L, Dekker N, Bamberg K, Schubert-Zsilavecz M, and Schwalbe H
- Subjects
- 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 genetics, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear chemistry
- 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.
- Published
- 2019
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