ArticleMolecular endocrinology (Baltimore, Md.)2011
Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange.
Article in Molecular endocrinology (Baltimore, Md.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 52 citations in OpenAlex.
- Nuclear receptor corepressor 1 levels differentially impact the intracellular dynamics of mutant thyroid hormone receptors associated with resistance to thyroid hormone syndrome.Molecular and cellular endocrinology · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Mediator subunit MED1 differentially modulates mutant thyroid hormone receptor intracellular dynamics in Resistance to Thyroid Hormone syndrome.Molecular and cellular endocrinology · 2023Article
- Protein-ligand binding with the coarse-grained Martini model.Nature communications · 2020Article
- Anthropogenic stressors impact fish sensory development and survival via thyroid disruption.Nature communications · 2020Article
- Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer.Medicinal research reviews · 2020Review
- Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor.Journal of cellular biochemistry · 2020Article
- Thyroid hormone receptor localization in target tissues.The Journal of endocrinology · 2018Review
- Analysis of Thyroid Tumorigenesis in Xenograft Mouse Model.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives.PPAR research · 2018Article
- Article
- How α-Helical Motifs Form Functionally Diverse Lipid-Binding Compartments.Annual review of biochemistry · 2017Review
- An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position.Scientific reports · 2017Article
- Futures Challenges in Thyroid Hormone Signaling Research.Frontiers in endocrinology · 2016Review
- Formation of a Ternary Complex for Selenocysteine Biosynthesis in Bacteria.The Journal of biological chemistry · 2015Article
- Oncogenic mutations of thyroid hormone receptor β.Oncotarget · 2015Article
- RXR agonist modulates TR: corepressor dissociation upon 9-cis retinoic acid treatment.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Nuclear receptor full-length architectures: confronting myth and illusion with high resolution.Trends in biochemical sciences · 2015Article
- Thyroid hormone receptors and resistance to thyroid hormone disorders.Nature reviews. Endocrinology · 2014Review
- Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone.Biochimica et biophysica acta · 2014Article
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains important to understand apo-LBD conformation and the way that it rearranges with ligands to develop better TR pharmaceuticals. In this study, we conducted hydrogen/deuterium exchange on TR LBDs with or without agonist (T(3)) or antagonist (NH3). Both ligands reduce deuterium incorporation into LBD amide hydrogens, implying tighter overall folding of the domain. As predicted, mass spectroscopic analysis of individual proteolytic peptides after hydrogen/deuterium exchange reveals that ligand increases the degree of solvent protection of regions close to the buried ligand-binding pocket. However, there is also extensive ligand protection of other regions, including the dimer surface at H10-H11, providing evidence for allosteric communication between the ligand-binding pocket and distant interaction surfaces. Surprisingly, C-terminal activation helix H12, which is known to alter position with ligand, remains relatively protected from solvent in all conditions suggesting that it is packed against the LBD irrespective of the presence or type of ligand. T(3), but not NH3, increases accessibility of the upper part of H3-H5 to solvent, and we propose that TR H12 interacts with this region in apo-TR and that this interaction is blocked by T(3) but not NH3. We present data from site-directed mutagenesis experiments and molecular dynamics simulations that lend support to this structural model of apo-TR and its ligand-dependent conformational changes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.