Ligand-Induced Allosteric Effects Governing SR Signaling

Abstract

Steroid receptors (SRs) are a class of ligand-regulated transcription factors that regulate gene expression in response to the binding of steroid hormones. Ligand binding drives conformational changes within the SR ligand binding domain that alters the receptors' affinity for coregulator proteins that in turn modulate chromatin state and either promote or block the recruitment of transcriptional machinery to a gene. Structural characterizations of SRs have provided insight into how these conformational rearrangements modulate receptor function, including signaling between the ligand binding pocket and the site of coregulator binding. Here, we review some of the proposed structural mechanisms put forward to explain the ability of ligands to modulate SR function. We also provide a discussion on computational methods that have contributed to the elucidation of SR allosteric regulation. Finally, we consider broader discussions of allostery within the SR family, such as receptor-induced reverse allostery and allosteric binding sites located outside of the canonical ligand interaction site.

Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

“…Crystal structures of GR LBD in complex with different ligands and coregulator peptides have shown that the receptor can adopt different conformations (5)(6)(7)9). In particular, the position of helix 12 is of key importance for receptor activity across the nuclear hormone receptor family (13)(14)(15)(16)(17). Recent reports on one other nuclear hormone receptor, the peroxisome proliferator-activated receptor  (PPAR), have demonstrated that helix 12 and the coregulatorbinding surface adopt an ensemble of conformations, the relative populations of which respond to ligand binding (18)(19)(20).…”

Rewiring Ancient Residue Interaction Networks Drove the Evolution of Specificity in Steroid Receptors

“…A poorly understood phenomenon in protein evolution is how dynamical features are altered as proteins evolve new function. SRs are allosterically regulated; ligand binding induces a conformational switch that triggers a host of downstream transcriptional events (Okafor et al, 2019). This allosteric mechanism is conserved in two early ancestors of the SR family (Thornton, 2001(Thornton, , 2004Thornton et al, 2003).…”

Structural Mechanism Underlying Ligand Binding and Activation of PPARγ

“…For example, in the absence of ligand, the PPARγ LBD is conformationally dynamic, samples multiple conformation, and binding of an agonist stabilizes the LBD in an active conformation to a degree correlated with the activity of the ligand (18,(23)(24)(25). The association between ligand-bound NR LBD conformation and graded function is evidence for conformational selection in the mechanism of NR ligand activity (13,15,(19)(20)(21)(22)53). However, these studies only address the functional mechanism of the ligand-bound state; they do not address the mechanism of ligand binding.…”

“…Molecular simulations of ligand binding to steroid receptors including androgen receptor (AR), estrogen receptor alpha (ERα), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR) also suggest an induced fit mechanism (9,10), although the site of ligand entry into the orthosteric pocket is different than FXR (7) and PPARγ (8). Indeed, ligand binding to nuclear receptors is often described to induce an active conformation (4,(11)(12)(13)(14)(15)(16). However, there is evidence from NMR studies on PPARγ that in the absence of ligand the apo-LBD exchanges between transcriptionally active and transcriptionally inactive/repressive conformations (17) suggesting a role for conformational selection in the ligand binding mechanism of NR agonists, which are thought to stabilize an active conformation from a dynamic ensemble of active and inactive/repressive conformations (15,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”