Gaining ligand selectivity in thyroid hormone receptors via entropy

Leandro Martínez, Alessandro S. Nascimento, Fabio M. Nunes, Kevin Phillips, Ricardo Aparicio, Sandra Martha G. Dias, Ana Carolina M. Figueira, Jean H. Lin, Phuong Nguyen, James W. Apriletti, Francisco A.R. Neves, John D. Baxter, Paul Webb, Munir S. Skaf, Igor Polikarpov

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor β (TRβ) vs. TRα reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRβ-selective binding. Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the atomic level; preferential binding depends on a nonconserved residue (Asn-331β) in the TRβ ligand-binding cavity (LBC), and GC-24 gains extra selectivity from insertion of a bulky side group into an extension of the LBC that only opens up with this ligand. Here we report that the natural TH 3,5,3′-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TRα selectivity. TR x-ray structures reveal better fit of ligand with the TRα LBC. The TRβ LBC, however, expands relative to TRα in the presence of Triac (549 Å3 vs. 461 Å3), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRβ and permits greater flexibility of the Triac carboxylate group in TRβ than in TRα. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRβ, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.

Original languageEnglish (US)
Pages (from-to)20717-20722
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - Dec 8 2009


  • Design
  • Mobility
  • Triac

ASJC Scopus subject areas

  • General


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