The multimerization pathway of the glucocorticoid receptor

Area of Science:

• Structural biology
• Molecular cell biology
• Pharmacology

Background:

• The glucocorticoid receptor (GR) is a crucial drug target for inflammatory and immunosuppressive conditions.
• The precise oligomeric conformation of full-length GR (FL-GR) is vital for its biological activity but remains debated.
• Understanding GR structure is key to developing effective therapies and treating resistance.

Purpose of the Study:

• To elucidate the functional oligomeric conformation of the glucocorticoid receptor (GR).
• To present a novel crystal structure of the agonist-bound GR ligand-binding domain (GR-LBD).
• To investigate the biological relevance of the identified dimer in receptor multimerization and cellular activity.

Main Methods:

• X-ray crystallography to determine the structure of agonist-bound GR-LBD.
• Molecular dynamics simulations to analyze receptor behavior.
• Crosslinking-mass spectrometry to study protein interactions.
• Fluorescence microscopy and transcriptomic analysis in living cells to assess biological relevance.

Main Results:

• A new crystal structure of agonist-bound GR-LBD revealed eight copies of a noncanonical dimer.
• The biological relevance of this dimer in FL-GR multimerization was confirmed using multiple experimental techniques.
• Self-association of the GR-LBD dimer in distinct assemblies provided insights into FL-GR multimerization.
• A comprehensive model for multidomain GR structure and oligomerization was proposed.

Conclusions:

• The study presents a novel GR-LBD dimer structure and a detailed oligomerization pathway for FL-GR.
• This model reconciles existing structural and functional data on GR.
• The findings offer a deeper understanding of generalized glucocorticoid resistance, a rare disorder affecting GR signaling.