The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Nuclear receptors (NRs) are ligand-responsive transcription factors controlling vital biological processes.
• NR function relies on ligand-induced conformational changes transmitting signals from the ligand-binding pocket to the activation function surface (AFS).
• The precise mechanisms of this allosteric communication remain incompletely understood.

Purpose of the Study:

• To elucidate the allosteric communication networks governing the activation of liver receptor homolog-1 (LRH-1).
• To understand how different ligands mediate communication to the AFS for distinct transcriptional outcomes.
• To explore the role of LRH-1 in development, metabolism, cancer, and inflammation.

Main Methods:

• Extensive all-atom molecular dynamics simulations (>100 μs) of 74 distinct LRH-1 complexes.
• Analysis of signaling circuits and allosteric communication pathways.
• Investigation of ligand-receptor and ligand-coregulator interactions.

Main Results:

• Identification of distinct allosteric signaling circuits used by active versus inactive LRH-1 ligands.
• Inactive ligands utilize strong, coordinated motions for AFS communication; activating ligands disrupt this and engage a second allosteric site.
• Ligand-contacting residues in helix 7 are crucial for switching between these communication circuits; inappropriate ligand-coregulator pairings induce destabilizing fluctuations.

Conclusions:

• Novel features of LRH-1 allosteric signaling have been uncovered, highlighting distinct pathways for ligand-mediated activation.
• The findings suggest potential therapeutic strategies targeting LRH-1 by modulating these allosteric circuits.
• The quantitative simulation approach provides a versatile framework for studying allosteric signaling in other nuclear receptors.