Structural basis of glucocorticoid receptor signaling bias

Abstract

Dissociation between the healthy and toxic effects of cortisol, a major stress‐responding hormone has been a widely used strategy to develop anti‐inflammatory glucocorticoids with fewer side effects. Such strategy falls short when treating brain disorders as timing and activity state within large‐scale neuronal networks determine the physiological and behavioral specificity of cortisol response. Advances in structural molecular dynamics posit the bases for engineering glucocorticoids with precision bias for select downstream signaling pathways. Design of allosteric and/or cooperative control for the glucocorticoid receptor could help promote the beneficial and reduce the deleterious effects of cortisol on brain and behavior in disease conditions.

Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?

“…The levels of FKBP51 are higher in the brains of AD subjects compared to age‐matched controls, suggesting that inhibitors of FKBP51 are desirable to restore GR functions in aging; 134 (v) the GR‐regulated gene Kfl9 that acts as transcription factor reduces glucocorticoid efficacy under duress in mice, and genome editing‐based silencing of KLF9 prevented the effects of chronic stress on brain and behavior; 135 and (vi) GR signaling through the BDNF‐dependent phosphorylation pathway deleted in knock‐in mice impaired the expression of specific target genes including Nr4a1 , Dusp1 and Sgk1 contrary to Fkbp51 and Gilz that remained unchanged 40,136 . These findings covering a non‐exhaustive list of GR‐regulated genes indicate that some targets are upregulated and others downregulated in AD, suggesting that GR ligands promoting biased signaling properties (e.g., rapid non‐genomic vs. slow genomic) are desirable to restore GR functions with lesser side effects 52 . Structural cooperativity between GR pharmacophore and allosteric sites modifiable by phosphorylation sets the basis for promoting signaling pathway specificity expected to vary between different tissues and cell types 137 .…”

“…51 By assisting the structural folding of the N-terminal domain from intrinsic entropy to acquired order, phosphorylation acts as prerequisite for docking signaling effectors. 52 The numerous GR phosphorylation sites classified according to glucocorticoid dependency, kinases and phosphatase specificity form a code linking post-translational modifications with 3D structures that GR can adopt reversibly, in various cellular environments. 53 The most characterized are the: (i) neurotrophindependent sites that are brain specific and neurocentric, and (ii) glucocorticoid-dependent sites that are widespread across organs and cell types.…”

“…30 With glucocorticoids on board all the time at naturally occurring oscillating levels, 95,116 allosteric modulators should in theory be safer to use than molecules with full agonistic or antagonistic activities given that GR signaling can be paired with neural activity. 52 Selective GR modulators like CORT108297 and CORT113176 that can act as partial antagonists and inverse agonists in distinct tissues or brain regions prevented the persistent rise of plasma glucocorticoid concentration and behavioral deficits induced by intracerebrovascular injection of amyloid-β oligomers. 117 Switching between positive and negative allosteric modulation does not necessarily require that the interactions between glucocorticoids and its pharmacophore differ.…”

“…118 It is the cooperativity between domains that sets the response evoked by structural transduction from the glucocorticoid-binding pocket where most GR ligands bind including agonists, antagonists and modulators. 52 New structural studies of GR interaction with select coactivators better defined the allosteric cavities to target in future high throughput screening for dissociative modulators. [119][120][121] Future ligands will be directed toward the unmet needs, that is not only the tissue or cellular specificity but also the dissociation between the non-genomic and the genomic glucocorticoid effects.…”

Editorial

“…As extensively demonstrated, glucorticoids are important regulators of nervous function. In this special issue, Jeanneteau and colleagues 11 discuss recent advances in structural molecular dynamics of glucocorticoid receptors. Meijer and colleagues 12 further discuss this topic taking into consideration transcriptional mechanisms at the levels of not only glucocorticoid, but also mineralocorticoid receptors, and their target genes that underly glucocorticoid effects in the brain.…”