A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function

Abstract

SummaryThe ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand-binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency, GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, and transcriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90-binding site. The alteration in the HSP90-binding site was accompanied by resistance to HSP90 antagonism, with persisting transactivation seen after geldanamycin treatment. Taken together, our studies reveal a new mechanism governing GR intracellular trafficking regulated by ligand binding that relies on a specific surface charge patch within the LBD. This conformational change permits extended GR action, probably because of altered GR-HSP90 interaction. This chemical series may offer anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics.

The Role of the Body Clock in Asthma and COPD: Implication for Treatment

“…Each of these 'peripheral' clocks can track light and dark through messages received from the 'central clock' or pacemaker in the suprachiasmatic nucleus of the brain. The central pacemaker integrates light and dark information and relays the information downstream by a network involving neural pathways, hormone release (glucocorticoids), and metabolic cues from rhythmic feeding behavior [8,9]. Light is the key entrainment factor for the SCN and feedingregulated metabolic cues are pivotal for the regulation of many peripheral clocks [8,9] Both central and peripheral clocks use the same molecular machinery to ''time'' the day.…”

“…The central pacemaker integrates light and dark information and relays the information downstream by a network involving neural pathways, hormone release (glucocorticoids), and metabolic cues from rhythmic feeding behavior [8,9]. Light is the key entrainment factor for the SCN and feedingregulated metabolic cues are pivotal for the regulation of many peripheral clocks [8,9] Both central and peripheral clocks use the same molecular machinery to ''time'' the day. Interlocking repressing and activating transcriptional and translational feedback loops culminate in the approximately 24-h rhythmic expression and activity of a set of core clock genes in each organ.…”

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

“…Although the conformational states of unliganded steroid receptor proteins remain poorly characterized, crystal structures of various ligand-bound states demonstrate that the conformational transitions of the ligand binding domain which are induced by steroid antagonists generally differ from those induced by steroid agonists, and these distinct conformations can differentially interact with co-regulators (17). In addition, a concurrent conformational transition in the Hsp90 subunits has been proposed to serve as a component of a larger scale allosteric response (18).…”

Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells

“…It should be noted that basal NIK stability has been observed in primary human cells indicating that not all signaling within this pathway may solely depend on receptor stimulation (Razani et al, 2011). It was also demonstrated that conformational changes induced by novel glucocorticoid receptor (GR) ligands can mediate new mechanisms of GR regulation (Trebble et al, 2013). Mapracorat is a ligand for GRs (Schacke et al, 2007) and may trigger conformation changes that enable rapid activation, leading to changes in transcriptional activity, or recruitment or replacement of accessory proteins that govern GR signaling outcomes.…”