Molecular tuning of farnesoid X receptor partial agonism

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-Zsilavecz and Harald Schwalbe ()
Additional contact information
Daniel Merk: Goethe University
Sridhar Sreeramulu: Goethe University
Denis Kudlinzki: Goethe University
Krishna Saxena: Goethe University
Verena Linhard: Goethe University
Santosh L. Gande: Goethe University
Fabian Hiller: Goethe University
Christina Lamers: Goethe University
Ewa Nilsson: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Anna Aagaard: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Lisa Wissler: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Niek Dekker: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Krister Bamberg: Innovative Medicines and Early Development Biotech Unit, AstraZeneca
Manfred Schubert-Zsilavecz: Goethe University
Harald Schwalbe: Goethe University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-10853-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10853-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-10853-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().