Structural basis for retinoic X receptor repression on the tetramer

Area of Science:

• Molecular biology
• Structural biology
• Cellular homeostasis

Background:

• Retinoic X receptor (RXR) is crucial for cell development and homeostasis.
• RXR exists as an autorepressed tetramer, activated by agonists.
• Mechanisms of RXR corepressor recruitment and antagonist repression remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of RXR repression.
• To determine the structural basis for corepressor and antagonist binding to RXR.
• To propose a molecular model for RXR repression.

Main Methods:

• X-ray crystallography was used to determine the structure of RXRα ligand-binding domain (LBD) complexes.
• Structures were determined for RXRαLBD with a silencing mediator for retinoid and thyroid hormone receptors (SMRT) corepressor motif.
• Structures were also determined for RXRαLBD-SMRT complexed with the antagonist rhein.

Main Results:

• The crystal structure of RXRαLBD-SMRT revealed significant structural rearrangement compared to the apo form.
• The RXRαLBD-SMRT-rhein structure showed two rhein molecules and two SMRT peptides bound to the tetramer.
• Rhein appears to displace SMRT motifs via interaction with the activation function 2 (AF-2) motif.
• RXRαLBD utilizes an overlapped binding site for coactivators, corepressors, and AF-2 motifs.
• The AF-2 motif adopts distinct conformations for agonist/antagonist interactions and coactivator/corepressor recruitment.

Conclusions:

• A molecular model for RXR repression on the tetramer is proposed.
• Structural insights clarify the distinct roles of AF-2 conformations in RXR regulation.
• This work advances the understanding of nuclear receptor-mediated gene regulation.