ArticleProceedings of the National Academy of Sciences of the United States of America2009
Gaining ligand selectivity in thyroid hormone receptors via entropy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 85 citations in OpenAlex.
- Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement.Thyroid : official journal of the American Thyroid Association · 2014Guideline
- American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models.Thyroid : official journal of the American Thyroid Association · 2014Guideline
- Article
- Developmental effects of sulfated thyroid hormones in sea urchin skeletogenesis suggest activation of non-canonical thyroid hormone signaling pathway.Frontiers in endocrinology · 2025Article
- Canagliflozin alleviates progestin resistance by suppressing RARβ/CRABP2 signaling in THRB knockout endometrial cancer cells.Frontiers in pharmacology · 2025Article
- Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs.iScience · 2023Article
- Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.Acta biochimica et biophysica Sinica · 2022Article
- A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers.Journal of biomolecular structure & dynamics · 2022Article
- Orthogonal fluorescent chemogenetic reporters for multicolor imaging.Nature chemical biology · 2021Article
- Structural insights revealed by two novel THRB mutations.Endocrine · 2020Article
- Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance.iScience · 2019Article
- Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists.Thyroid : official journal of the American Thyroid Association · 2019Review
- Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library.Environmental health perspectives · 2019Article
- The Colorful Diversity of Thyroid Hormone Metabolites.European thyroid journal · 2019Review
- Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions.Stem cells international · 2019Review
- CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands.International journal of molecular sciences · 2016Article
- Dynamic Structure and Inhibition of a Malaria Drug Target: Geranylgeranyl Diphosphate Synthase.Biochemistry · 2016Article
- Article
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Authors and funding
15 authors at 7 institutions in 2 countries.
Funding
Abstract
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 beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRbeta-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-331beta) in the TRbeta 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 TRbeta selectivity. TR x-ray structures reveal better fit of ligand with the TRalpha LBC. The TRbeta LBC, however, expands relative to TRalpha in the presence of Triac (549 A(3) vs. 461 A(3)), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRbeta and permits greater flexibility of the Triac carboxylate group in TRbeta than in TRalpha. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRbeta, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.
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