Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new...

Area of Science:

• Structural biology
• Immunology
• Pharmacology

Background:

• Retinoic acid-related orphan receptor gamma (RORγ) is a key regulator of T helper 17 (Th17) cells, which are implicated in autoimmune diseases.
• Inhibitors targeting the RORγ ligand binding domain (LBD) are promising therapeutic agents for autoimmune disorders.
• Structure-based drug design has successfully identified RORγ inhibitors.

Purpose of the Study:

• To elucidate the structural basis of a novel RORγ inhibitor, compound T, in complex with RORγ-LBD and a corepressor peptide.
• To understand the mechanism of action of compound T and compare it with previously identified inverse agonists.
• To provide insights for the development of new drugs targeting RORγ for autoimmune diseases.

Main Methods:

• X-ray crystallography was used to determine the co-complex structure of RORγ-LBD, compound T, and a corepressor peptide.
• Structural analysis focused on conformational changes induced by compound T binding.
• Comparison of the ternary complex structure with previously reported RORγ-inverse agonist complexes.

Main Results:

• The crystal structure of the ternary complex revealed a novel inhibitory mechanism mediated by compound T.
• Compound T induced a ~2 Å shift in helix 5 (H5) backbone and conformational changes in Met365.
• These structural alterations led to reduced binding of the corepressor peptide to RORγ-LBD, suggesting H5 shift is critical for inhibition.

Conclusions:

• The novel RORγ inhibitor compound T employs a distinct mechanism of action compared to inverse agonists.
• The observed conformational changes, particularly the H5 shift, are crucial for the inhibitory effect.
• This structural understanding provides a foundation for designing more effective RORγ-targeted therapies for autoimmune conditions.