Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions

Area of Science:

• Molecular Endocrinology
• Nuclear Receptor Research
• Pharmacology

Background:

• Estrogen receptor-related receptor-alpha (ERRalpha) is an orphan nuclear receptor.
• ERRalpha interacts with coactivators without a classical ligand, functioning constitutively.
• Coactivator recruitment is crucial for nuclear receptor transcriptional activity.

Purpose of the Study:

• To probe the ERRalpha-coactivator interaction pocket architecture.
• To identify peptides selectively interacting with ERRalpha.
• To understand the mechanistic differences in coactivator recruitment by ERRalpha.

Main Methods:

• Screening of combinatorial phage libraries for selective peptide binders.
• Characterization of peptide-ERRalpha interactions.
• Comparative analysis of ERRalpha coactivator binding mechanisms.

Main Results:

• Identified peptides that selectively interact with ERRalpha.
• Uncovered a fundamental difference in ERRalpha's interaction with PGC-1alpha versus SRC coactivators.
• Demonstrated ERRalpha's unique coactivator binding mechanism.

Conclusions:

• ERRalpha exhibits a distinct mechanism for coactivator interaction compared to steroid receptor coactivators.
• Development of ERRalpha ligands with differential pharmacological activities is feasible by modulating coactivator recruitment.
• Alterations in the activation function-2 pocket of nuclear receptors can lead to differential coactivator recruitment, with significant pharmaceutical implications.