ArticleCellular and molecular life sciences : CMLS2011
Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor.
Article in Cellular and molecular life sciences : CMLS, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Ultrarapid MC1R protein and associated plumage color evolution in the domestic chicken.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.JCI insight · 2024Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Receptor modulators associated with the hypothalamus -pituitary-thyroid axis.Frontiers in pharmacology · 2023Review
- Modulating TSH Receptor Signaling for Therapeutic Benefit.European thyroid journal · 2020Article
- A Gq Biased Small Molecule Active at the TSH Receptor.Frontiers in endocrinology · 2020Article
- TSH Receptor Homodimerization in Regulation of cAMP Production in Human ThyrocytesFrontiers in endocrinology · 2020Article
- Structure and activation of the TSH receptor transmembrane domain.Auto- immunity highlights · 2017Article
- Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.Frontiers in endocrinology · 2017Review
- Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies.Expert opinion on therapeutic targets · 2015Review
- New small molecule agonists to the thyrotropin receptor.Thyroid : official journal of the American Thyroid Association · 2015Article
- Allosteric modulators hit the TSH receptor.Endocrinology · 2014Article
- The W520X mutation in the TSHR gene brings on subclinical hypothyroidism through an haploinsufficiency mechanism.Journal of endocrinological investigation · 2013Article
- Novel insights on thyroid-stimulating hormone receptor signal transduction.Endocrine reviews · 2013Review
- Small-molecule screening identifies modulators of aquaporin-2 trafficking.Journal of the American Society of Nephrology : JASN · 2013Article
- Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists.Biochemical Society transactions · 2013Review
- Update in TSH receptor agonists and antagonists.The Journal of clinical endocrinology and metabolism · 2012Review
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Authors and funding
9 authors.
Funding
Abstract
The thyrotropin receptor (TSHR) exhibits elevated cAMP signaling in the basal state and becomes fully activated by thyrotropin. Previously we presented evidence that small-molecule ligands act allosterically within the transmembrane region in contrast to the orthosteric extracellular hormone-binding sites. Our goal in this study was to identify positions that surround the allosteric pocket and that are sensitive for inactivation of TSHR. Homology modeling combined with site-directed mutagenesis and functional characterization revealed seven mutants located in the allosteric binding site that led to a decrease of basal cAMP signaling activity. The majority of these silencing mutations, which constrain the TSHR in an inactive conformation, are found in two clusters when mapped onto the 3D structural model. We suggest that the amino acid positions identified herein are indicating locations where small-molecule antagonists, both neutral antagonists and inverse agonists, might interfere with active TSHR conformations.
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