How nuclear receptors transition between active and inactive forms: An energetic perspective.

Area of Science:

• Molecular biology
• Structural biology
• Computational chemistry

Background:

• Nuclear receptors control gene expression via ligand binding.
• Ligand binding induces conformational changes, particularly in helix 12 (H12), to regulate receptor activity.
• The precise nature of inactive states and ligand-induced transitions remains incompletely understood.

Purpose of the Study:

• To investigate the timescale and energy landscape of progesterone receptor (PR) conformational transitions.
• To elucidate how different ligands (partial agonist, agonist, antagonist) affect these transitions.

Main Methods:

• Accelerated molecular dynamics (MD) simulations were employed.
• Analysis focused on the conformational changes of the progesterone receptor (PR).
• Energetic analysis was performed to characterize the transition barriers between states.

Main Results:

• Microsecond MD simulations were insufficient to observe PR state transitions.
• Millisecond timescales, achieved via accelerated MD, revealed transitions from inactive to active PR states.
• Both active and inactive PR conformations represent distinct energy minima.
• Ligand identity significantly influences the energy landscape, with agonists/antagonists showing minimal transition.

Conclusions:

• The conformational transition of nuclear receptors requires millisecond timescales.
• Ligand identity is a critical determinant of the energy landscape and receptor state dynamics.
• Understanding these dynamics is key to developing targeted therapies.