Nuclear Receptor Interdomain Communication is Mediated by the Hinge with Ligand Specificity

[Display omitted] •In this work, we seek to understand interdomain communication in a nuclear receptor.•Simulations reveal ligand-induced interdomain contact in the farnesoid X receptor.•Experiments validate ligand-induced interdomain contact in FXR.•The hinge domain plays a critical role in mediating interdomain contact.•This work provides a framework to study interdomain dynamics in other receptors. Nuclear receptors are ligand-induced transcription factors that bind directly to target genes and regulate their expression. Ligand binding initiates conformational changes that propagate to other domains, allosterically regulating their activity. The nature of this interdomain communication in nuclear receptors is poorly understood, largely owing to the difficulty of experimentally characterizing full-length structures. We have applied computational modeling approaches to describe and study the structure of the full-length farnesoid X receptor (FXR), approximated by the DNA binding domain (DBD) and ligand binding domain (LBD) connected by the flexible hinge region. Using extended molecular dynamics simulations (>10 microseconds) and enhanced sampling simulations, we provide evidence that ligands selectively induce domain rearrangement, leading to interdomain contact. We use protein–protein interaction assays to provide experimental evidence of these interactions, identifying a critical role of the hinge in mediating interdomain contact. Our results illuminate previously unknown aspects of interdomain communication in FXR and provide a framework to enable characterization of other full-length nuclear receptors.