Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Nuclear hormone receptors (NRs) are critical ligand-activated transcription factors involved in cellular regulation.
• Dimerization, particularly of the ligand-binding domain (LBD), is essential for NR function.
• The dimeric structure of the glucocorticoid receptor-alpha (GRα) LBD is debated, unlike the well-characterized estrogen receptor-alpha (ERα) LBD dimer.

Purpose of the Study:

• To re-evaluate the physiologically relevant dimeric structure of the GRα LBD.
• To compare GRα LBD dimer stability and conservation with the ERα LBD dimer.
• To identify potential alternative GRα LBD dimeric architectures.

Main Methods:

• Analysis of crystal structures of GRα LBD homodimers.
• Energetic analysis using PISA and MM/PBSA computational methods.
• Sequence conservation analysis comparing GRα and ERα LBD dimers.

Main Results:

• The commonly accepted GRα LBD dimer assembly exhibits weak stability and lacks significant residue conservation.
• An alternative GRα LBD homodimer, involving helix 9 and C-terminal residues, shows higher stability and conservation.
• No observed GRα LBD crystal dimer is as stable or conserved as the ERα LBD dimer, with the GRα C-terminal F-domain hindering canonical dimerization.

Conclusions:

• The current understanding of the GRα homodimer structure requires re-examination.
• Experimental investigation into alternative GRα LBD dimer architectures is warranted.
• Findings impact the interpretation of GRα physiological data and glucocorticoid-based therapeutic strategies.