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Updated: May 11, 2026
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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
Published on: September 21, 2011
A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function
Peter J Trebble1, James M Woolven, Ken A Saunders
1Manchester Centre for Nuclear Hormone Research in Disease, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Journal of Cell Science
|May 21, 2013
Summary
New non-steroidal glucocorticoid receptor (GR) ligands, GSK47867A and GSK47869A, offer prolonged anti-inflammatory action by altering GR conformation and HSP90 interaction, not pharmacokinetics.
Area of Science:
- Pharmacology
- Molecular Biology
- Drug Discovery
Background:
- The glucocorticoid receptor (GR) is a key target for inflammatory diseases.
- Current GR drugs face challenges in specificity and tissue sensitivity.
Purpose of the Study:
- To identify novel, non-steroidal GR ligands with improved therapeutic potential.
- To elucidate the mechanism behind the prolonged cellular action of these new ligands.
Main Methods:
- Identification and characterization of novel non-steroidal GR ligands (GSK47867A, GSK47869A).
- Analysis of GR ligand-binding domain (LBD) conformation and intracellular trafficking.
- Investigation of GR interaction with HSP90 and response to HSP90 antagonism.
Main Results:
- GSK47867A and GSK47869A are high-potency, non-steroidal GR ligands.
- These ligands induce a novel GR LBD conformation, leading to slow nuclear translocation and prolonged nuclear retention.
- The ligands alter the GR LBD structure at the HSP90-binding site, conferring resistance to HSP90 antagonism and enabling sustained transactivation.
Conclusions:
- A new mechanism of GR intracellular trafficking, regulated by ligand-induced conformational changes at the HSP90-binding site, has been revealed.
- This mechanism leads to extended GR action via altered GR-HSP90 interactions.
- This chemical series presents potential for anti-inflammatory drugs with prolonged duration of action based on pharmacodynamic rather than pharmacokinetic alterations.
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