Gaining ligand selectivity in thyroid hormone receptors via entropy

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Nuclear receptors are crucial pharmaceutical targets, but achieving subtype selectivity is challenging due to conserved structures.
• Thyroid hormone receptor beta (TRbeta)-selective ligands offer therapeutic benefits like reduced cholesterol without cardiac side effects.
• Previous TRbeta-selective ligands exploit specific amino acid residues and ligand-induced cavity modifications.

Purpose of the Study:

• To elucidate the molecular mechanism behind the subtype-selective binding of the natural thyroid hormone 3,5,3'-triodothyroacetic acid (Triac) to TRbeta.
• To understand how Triac achieves selectivity for TRbeta over TRalpha at an atomic level.
• To explore potential applications of this selectivity mechanism in designing novel nuclear receptor drugs.

Main Methods:

• X-ray crystallography to determine the structures of TRalpha and TRbeta bound to Triac.
• Molecular dynamics simulations to analyze ligand-receptor interactions and conformational changes.
• Thermodynamic analysis to assess binding free energy and entropic contributions.

Main Results:

• Triac fits better into the TRalpha ligand-binding cavity (LBC) than the TRbeta LBC.
• The TRbeta LBC significantly expands in the presence of Triac (549 A(3) vs. 461 A(3) for TRalpha).
• Water molecules occupy the expanded space in TRbeta, increasing solvation and compensating for weaker ligand interactions.
• Increased flexibility of the Triac carboxylate group in TRbeta leads to reduced entropic restraint and lower binding free energy.

Conclusions:

• Triac achieves TRbeta selectivity through a unique mechanism involving LBC expansion and increased solvation, rather than direct interaction optimization.
• This water-mediated, solvation-driven selectivity mechanism offers a novel approach for designing subtype-selective nuclear receptor modulators.
• The findings suggest that exploiting ligand-induced cavity dynamics and solvation effects could be a broadly applicable strategy in pharmaceutical drug design for nuclear receptors.