ArticleProceedings of the National Academy of Sciences of the United States of America2012
Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Conformational transition of a polycationic hinge domain contributes to DNA binding.Biophysical chemistry · 2026Article
- Hormone response elements for the thyroid receptor-α include specific distal 5'-flanking DNA.Science advances · 2024Article
- Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential.Frontiers in pharmacology · 2024Review
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Cooperativity as quantification and optimization paradigm for nuclear receptor modulators.Chemical science · 2022Article
- Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance.iScience · 2019Article
- Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR.The Journal of biological chemistry · 2018Article
- AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses.Nucleic acids research · 2018Article
- Allosteric pathways in nuclear receptors - Potential targets for drug design.Pharmacology & therapeutics · 2018Review
- Thyroid Hormone Resistance in Identical Twin Sisters with Atrial Fibrillation: Case Report and Review of the Literature.Journal of endocrinology and diabetes · 2018Article
- DNA-induced unfolding of the thyroid hormone receptor α A/B domain through allostery.FEBS open bio · 2017Article
- Retinoid X Receptors Intersect the Molecular Clockwork in the Regulation of Liver Metabolism.Frontiers in endocrinology · 2017Review
- The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor.The journal of physical chemistry. B · 2016Article
- A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1).Journal of medicinal chemistry · 2015Article
- Mapping allostery through computational glycine scanning and correlation analysis of residue-residue contacts.Biochemistry · 2015Article
- RXR agonist modulates TR: corepressor dissociation upon 9-cis retinoic acid treatment.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Agonist ligands mediate the transcriptional response of nuclear receptor heterodimers through distinct stoichiometric assemblies with coactivators.The Journal of biological chemistry · 2014Article
- Targeting nuclear receptors with marine natural products.Marine drugs · 2014Review
- Retinoic acid actions through mammalian nuclear receptors.Chemical reviews · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Thyroid hormones such as 3,3',5 triiodo-L-thyronine (T3) control numerous aspects of mammalian development and metabolism. The actions of such hormones are mediated by specific thyroid hormone receptors (TRs). TR belongs to the nuclear receptor family of modular transcription factors that binds to specific DNA-response elements within target promoters. These receptors can function as homo- or heterodimers such as TR:9-cis retinoic acid receptor (RXR). Here, we present the atomic resolution structure of the TRα•T3:RXRα•9-cis retinoic acid (9c) ligand binding domain heterodimer complex at 2.95 Å along with T3 hormone binding and dissociation and coactivator binding studies. Our data provide a structural basis for allosteric communication between T3 and 9c and negative cooperativity between their binding pockets. In this structure, both TR and RXR are in the active state conformation for optimal binding to coactivator proteins. However, the structure of TR•T3 within TR•T3:RXR•9c is in a relative state of disorder, and the observed kinetics of binding show that T3 dissociates more rapidly from TR•T3:RXR•9c than from TR•T3:RXR. Also, coactivator binding studies with a steroid receptor coactivator-1 (receptor interaction domains 1-3) fragment show lower affinities (K(a)) for TR•T3:RXR•9c than TR•T3:RXR. Our study corroborates previously reported observations from cell-based and binding studies and offers a structural mechanism for the repression of TR•T3:RXR transactivation by RXR agonists. Furthermore, the recent discoveries of multiple endogenous RXR agonists that mediate physiological tasks such as lipid biosynthesis underscore the pharmacological importance of negative cooperativity in ligand binding within TR:RXR heterodimers.
Indexed as
Identifiers
What OpenQuestion holds
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.