Allosteric communications between domains of nuclear receptors

Nuclear receptors (NRs) regulate gene expression in response to hormonal signals, influencing diverse physiological processes and diseases. Structural and dynamics investigations based on X-ray crystallography, cryo-electron microscopy (cryo-EM), hydrogen-deuterium exchange mass spectrometry, and molecular dynamics simulations, have significantly deepened our understanding of the conformational states, dynamics, and interdomain interactions of multi-domain NRs. Structural studies have examined heterodimeric complexes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) with retinoid X receptor alpha (RXRα), liver X receptor beta (LXRβ) with RXRα, and retinoic acid receptor beta (RARβ) with RXRα, as well as homodimers like hepatic nuclear factor 4 alpha (HNF-4α), androgen receptor (AR), and glucocorticoid receptor (GR). These investigations highlight critical allosteric communication between ligand-binding domains (LBDs) and DNA-binding domains (DBDs), emphasizing the roles of flexible hinge regions and N-terminal segments in adapting to diverse DNA configurations. Both non-steroid receptor heterodimers and homodimers exhibit robust interdomain connections that mediate allosteric signaling. For instance, AR demonstrates three distinct conformational states that underscore its dynamic behavior, while GR exhibits unique ligand-dependent domain interactions shaping receptor signaling. The collective findings so far suggest a conserved mechanism of cross-domain communication across the NR family. Supported by complementary biophysical, spectroscopic, mutagenesis, and computational studies, this body of research has elucidated the nature of domain-domain interfaces and their pivotal roles in regulating the transcriptional activity of steroid and non-steroid receptors.