TY - JOUR
T1 - Nuclear Receptor Interdomain Communication is Mediated by the Hinge with Ligand Specificity
AU - Hazarika, Saurov
AU - Yu, Tracy
AU - Biswas, Arumay
AU - Dube, Namita
AU - Villalona, Priscilla
AU - Okafor, C. Denise
N1 - Publisher Copyright:
© 2024
PY - 2024/11/15
Y1 - 2024/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205487349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85205487349&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2024.168805
DO - 10.1016/j.jmb.2024.168805
M3 - Article
C2 - 39332668
AN - SCOPUS:85205487349
SN - 0022-2836
VL - 436
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 22
M1 - 168805
ER -