Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators

Abstract

The bile-acid sensing nuclear farnesoid X receptor (FXR) is an attractive target for the treatment of hepatic and metabolic diseases, but application of this chemotherapeutic concept remains limited due to adverse effects of FXR activation observed in clinical trials. To elucidate the mechanistic basis of FXR activation at the molecular level, we have systematically studied FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands. Different molecular effects on FXR activation mediated by different scaffolds were evident and aligned with characteristic structural changes within the ligand binding domain of FXR. A partial FXR agonist acted mainly through co-repressor displacement from FXR and caused an FXR-regulated gene expression pattern markedly differing from FXR agonist effects. These results suggest selective modulation of FXR dimerization and co-regulator interactions for different ligands, offering a potential avenue for the design of gene-or tissueselective FXR modulators.

When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists

“…Interestingly, recent work from Heering et al . (2022) [15] suggests that partial agonism can be better understood on the differential co‐recruitment level, by favouring co‐repressor displacement, an aspect we have not investigated in this work.…”

“…We suggest S 1 /S 4 metastates represent the active conformations, while S 2 /S 3 /S 5 can be used to describe inactive/antagonistbound systems. Interestingly, recent work from Heering et al (2022) [15] suggests that partial agonism can be better understood on the differential co-recruitment level, by favouring co-repressor displacement, an aspect we have not investigated in this work.…”

“…[14] However, it was not until recently that the different interaction motifs and coregulatory proteins binding to different FXR-ligand combinations started to be discussed. [15] Classically, nuclear receptor antagonism has been structurally studied, mostly focusing on the receptor LBD. In the unliganded forms, α12 can assume either an extended conformation, pushed away from the LBD [16] or adopt multiple conformations in solution.…”

“…It is discussed for other NRs, that RXRα dimerization can change the co‐recruitment process (enhancing it) [14] . However, it was not until recently that the different interaction motifs and co‐regulatory proteins binding to different FXR‐ligand combinations started to be discussed [15] …”

Opportunities and challenges in targeting orphan nuclear receptors

“…1(b)). 27,30 In addition to agonists with varying levels of efficacy, NR activity can be modulated with antagonists that bind to the binding site of (endogenous) agonists and competitively prevent their binding without inducing conformational changes necessary for activation. Moreover, particularly receptors with constitutive activity can be blocked by inverse agonists that prevent the NR from adopting its (auto-)activated conformation.…”