ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2010
Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 45 citations in OpenAlex.
- Article
- Modeling TSH Receptor Dimerization at the Transmembrane Domain.Endocrinology · 2022Article
- A Gq Biased Small Molecule Active at the TSH Receptor.Frontiers in endocrinology · 2020Article
- Structure and activation of the TSH receptor transmembrane domain.Auto- immunity highlights · 2017Article
- GPCR-SSFE 2.0-a fragment-based molecular modeling web tool for Class A G-protein coupled receptors.Nucleic acids research · 2017Article
- Expanding the Role of Thyroid-Stimulating Hormone in Skeletal Physiology.Frontiers in endocrinology · 2017Review
- Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.Frontiers in endocrinology · 2017Review
- TSH Receptor Signaling Abrogation by a Novel Small Molecule.Frontiers in endocrinology · 2016Article
- 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
- Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor's Extracellular Hinge Region.Frontiers in endocrinology · 2015Article
- Computational studies to predict or explain G protein coupled receptor polypharmacology.Trends in pharmacological sciences · 2014Article
- Allosteric modulators hit the TSH receptor.Endocrinology · 2014Article
- Novel insights on thyroid-stimulating hormone receptor signal transduction.Endocrine reviews · 2013Review
- 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
- Allosteric model of maraviroc binding to CC chemokine receptor 5 (CCR5).The Journal of biological chemistry · 2011Article
- From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G-protein-coupled receptors (GPCRs).The Journal of biological chemistry · 2011Article
- Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor.Cellular and molecular life sciences : CMLS · 2011Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The thyrotropin receptor [thyroid-stimulating hormone receptor (TSHR)], a G-protein-coupled receptor (GPCR), is endogenously activated by thyrotropin, which binds to the extracellular region of the receptor. We previously identified a low-molecular-weight (LMW) agonist of the TSHR and predicted its allosteric binding pocket within the receptor's transmembrane domain. Because binding of the LMW agonist probably disrupts interactions or leads to formation of new interactions among amino acid residues surrounding the pocket, we tested whether mutation of residues at these positions would lead to constitutive signaling activity. Guided by molecular modeling, we performed site-directed mutagenesis of 24 amino acids in this spatial region, followed by functional characterization of the mutant receptors in terms of expression and signaling, measured as cAMP accumulation. We found that mutations V421I, Y466A, T501A, L587V, M637C, M637W, S641A, Y643F, L645V, and Y667A located in several helices exhibit constitutive activity. Of note is mutation M637W at position 6.48 in transmembrane helix 6, which has a significant effect on the interaction of the receptor with the LMW agonist. In summary, we found that a high proportion of residues in several helices surrounding the allosteric binding site of LMW ligands in the TSHR when mutated lead to constitutively active receptors. Our findings of signaling-sensitive residues in this region of the transmembrane bundle may be of general importance as this domain appears to be evolutionarily retained among GPCRs.
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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.