ArticleBiochemistry2008
Quantification of ligand-regulated nuclear receptor corepressor and coactivator binding, key interactions determining ligand potency and efficacy for the thyroid hormone receptor.
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
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- Multicolored, Tb³⁺-Based Antibody-Free Detection of Multiple Tyrosine Kinase Activities.Analytical chemistry · 2015Article
- Assessing dose-response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity.Environmental health : a global access science source · 2015Article
- Nuclear receptors and epigenetic regulation: opportunities for nutritional targeting and disease prevention.Advances in nutrition (Bethesda, Md.) · 2014Review
- Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study.Dose-response : a publication of International Hormesis Society · 2014Article
- Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
- Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.Bioorganic & medicinal chemistry · 2013Article
- Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.Endocrine reviews · 2012Review
- Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor β-selective ligands.Journal of medicinal chemistry · 2012Article
- Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities.The Journal of biological chemistry · 2011Article
- Structure of a thyroid hormone receptor DNA-binding domain homodimer bound to an inverted palindrome DNA response element.Molecular endocrinology (Baltimore, Md.) · 2010Article
- Minireview: Not picking pockets: nuclear receptor alternate-site modulators (NRAMs).Molecular endocrinology (Baltimore, Md.) · 2010Review
- Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways.The Journal of steroid biochemistry and molecular biology · 2009Article
- A dual-acceptor time-resolved Föster resonance energy transfer assay for simultaneous determination of thyroid hormone regulation of corepressor and coactivator binding to the thyroid hormone receptor: Mimicking the cellular context of thyroid hormone action.Analytical biochemistry · 2009Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The potency and efficacy of ligands for nuclear receptors (NR) result both from the affinity of the ligand for the receptor and from the affinity that various coregulatory proteins have for ligand-receptor complexes; the latter interaction, however, is rarely quantified. To understand the molecular basis for ligand potency and efficacy, we developed dual time-resolved fluorescence resonance energy transfer (tr-FRET) assays and quantified binding of both ligand and coactivator or corepressor to the thyroid hormone receptor (TR). Promoter-bound TR exerts dual transcriptional regulatory functions, recruiting corepressor proteins and repressing transcription in the absence of thyroid hormones (THs) and shedding corepressors in favor of coactivators upon binding agonists, activating transcription. Our tr-FRET assays involve a TRE sequence labeled with terbium (fluorescence donor), TRbeta.RXRalpha heterodimer, and fluorescein-labeled NR interaction domains of coactivator SRC3 or corepressor NCoR (fluorescence acceptors). Through coregulator titrations, we could determine the affinity of SRC3 or NCoR for TRE-bound TR.RXR heterodimers, unliganded or saturated with different THs. Alternatively, through ligand titrations, we could determine the relative potencies of different THs. The order of TR agonist potencies is as follows: GC-1 approximately T 3 approximately TRIAC approximately T 4 >> rT 3 (for both coactivator recruitment and corepressor dissociation); the affinities of SRC3 binding to TR-ligand complexes followed a similar trend. This highlights the fact that the low activity of rT 3 is derived both from its low affinity for TR and from the low affinity of SRC for the TR-rT 3 complex. The TR antagonist NH-3 failed to induce SRC3 recruitment but did effect NCoR dissociation. These assays provide quantitative information about the affinity of two key interactions that are determinants of NR ligand potency and efficacy.
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