Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal–)function, with Special Emphasis on the TSH Receptor

Abstract The thyrotropin receptor (TSHR), the lutropin- (LHR), and the follicotropin receptor (FSHR) belong to glycoprotein hormone receptors (GPHR), a subgroup of the class A G-protein coupled receptors. In this review, the unique features of GPHR have been taken into account for their pharmacological interventions: i) The respective hormone and stimulating or blocking antibodies are binding on the large ectodomain that is ii) via a hinge region, containing iii) an internal tethered agonist linked to the transmembrane domain. iv) Multimerization and mechanisms for negative or positive cooperativity of GPHR upon ligand binding and v) dimer- and oligomeric arrangements enabling trans-activation on GPHR signaling are considered. Available knowledge concerning the modulation of the GPHR (mal)-function and associated structural aspects by diverse entities such as antibodies, chaperones, peptides, small molecule agonists, inverse agonists, and antagonists is summarized. The TSHR is important with respect to autoimmune [Graves’ disease (GD), Graves’ orbitopathy (GO)] or non-autoimmune thyroid dysfunctions and cancer-development. To date there is neither an agonist nor antagonist modulator of pathogenic such as TSHR signaling in the clinics. However, several different ligands monoclonal stimulating and inhibiting antibodies and small molecule drug-like ligands have been reported in the last decade. In special focus are the most recent findings regarding the development and use of small molecule TSHR ligands. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts towards understanding the interplay of TSHR multimers, especially their interaction with drug-like ligands. Important in this context is the biased ligand development.

• Publication year

  2018

• Venue

  Hormone and Metabolic Research

• Publication date

  2018-10-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1055/a-0749-6528PMID 30366347
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors

  2018cited by this paper
• Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro

  2018cited by this paper
• Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges.

  2018cited by this paper
• Molecular mechanism of GPCR-mediated arrestin activation

  2018cited by this paper
• New Insights into Modes of GPCR Activation.

  2018cited by this paper
• Allosteric Regulation of the Follicle-Stimulating Hormone Receptor.

  2018influential reference
• Structural insights into G-protein-coupled receptor allostery

  2018cited by this paper
• Identifying G protein-coupled receptor dimers from crystal packings

  2018cited by this paper
• Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations

  2018cited by this paper
• Pharmacoperones for Misfolded Gonadotropin Receptors.

  2018influential reference
• Selectivity determinants of GPCR–G-protein binding

  2017cited by this paper
• Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

  2017cited by this paper
• How Ligands Illuminate GPCR Molecular Pharmacology.

  2017cited by this paper
• Structural Basis for G Protein-Coupled Receptor Activation.

  2017cited by this paper
• Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs.

  2017cited by this paper
• β-arrestin signalling and bias in hormone-responsive GPCRs.

  2017cited by this paper
• Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

  2017cited by this paper
• Teprotumumab for Thyroid‐Associated Ophthalmopathy

  2017cited by this paper
• Inheritable and sporadic non-autoimmune hyperthyroidism.

  2017cited by this paper
• Trends in GPCR drug discovery: new agents, targets and indications

  2017cited by this paper
• Nanobodies to Study G Protein-Coupled Receptor Structure and Function.

  2017cited by this paper
• GPCR-SSFE 2.0—a fragment-based molecular modeling web tool for Class A G-protein coupled receptors

  2017cited by this paper
• TSHR/IGF-1R Cross-Talk, Not IGF-1R Stimulating Antibodies, Mediates Graves' Ophthalmopathy Pathogenesis

  2017influential reference
• An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties

  2016cited by this paper
• Integrating structural and mutagenesis data to elucidate GPCR ligand binding.

  2016cited by this paper
• TSH Receptor Signaling Abrogation by a Novel Small Molecule

  2016cited by this paper
• Evidence for the heterotetrameric structure of the adenosine A2A-dopamine D2 receptor complex.

  2016cited by this paper
• Profiling of FSHR negative allosteric modulators on LH/CGR reveals biased antagonism with implications in steroidogenesis.

  2016cited by this paper
• TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis.

  2016influential reference
• Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation*

  2016cited by this paper
• The Follitropin Receptor: Matching Structure and Function

  2016cited by this paper
• TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.

  2016cited by this paper
• The Effect of Early Thyroidectomy on the Course of Active Graves’ Orbitopathy (GO): A Retrospective Case Study

  2016cited by this paper
• Comparison of Efficacy and Adverse Effects Between Methimazole 15 mg+Inorganic Iodine 38 mg/Day and Methimazole 30 mg/Day as Initial Therapy for Graves' Disease Patients with Moderate to Severe Hyperthyroidism

  2015cited by this paper
• Single-Molecule Analyses of Fully Functional Fluorescent Protein-Tagged Follitropin Receptor Reveal Homodimerization and Specific Heterodimerization with Lutropin Receptor1

  2015influential reference
• Novel Allosteric Modulators of G Protein-coupled Receptors*

  2015cited by this paper
• Two disparate ligand-binding sites in the human P2Y1 receptor

  2015cited by this paper
• Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors

  2015cited by this paper
• Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor’s Extracellular Hinge Region

  2015cited by this paper
• Structures of G protein-coupled receptors reveal new opportunities for drug discovery.

  2015cited by this paper
• TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist

  2015cited by this paper
• New Small Molecule Agonists to the Thyrotropin Receptor

  2015cited by this paper
• Future Prospects for the Treatment of Graves’ Hyperthyroidism and Eye Disease

  2015influential reference
• Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

  2015influential reference
• The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases*♦

  2015cited by this paper
• Mechanisms of Action of TSHR Autoantibodies

  2015influential reference
• β‐Arrestin‐1 mediates thyrotropin‐enhanced osteoblast differentiation

  2014cited by this paper
• Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer

  2014influential reference
• Single Molecule Analysis of Functionally Asymmetric G Protein-coupled Receptor (GPCR) Oligomers Reveals Diverse Spatial and Structural Assemblies*♦

  2014cited by this paper
• TSH Receptor Mutations and Diseases

  2014cited by this paper
• A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.

  2014cited by this paper
• Pharmacological chaperoning: a primer on mechanism and pharmacology.

  2014cited by this paper
• Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

  2014cited by this paper
• Molecular signatures of G-protein-coupled receptors

  2013cited by this paper
• Di/oligomerization of GPCRs-mechanisms and functional significance.

  2013cited by this paper
• Novel insights on thyroid-stimulating hormone receptor signal transduction.

  2013cited by this paper
• Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor.

  2013cited by this paper
• Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists

  2013cited by this paper
• Modern methods to investigate the oligomerization of glycoprotein hormone receptors (TSHR, LHR, FSHR).

  2013cited by this paper
• A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy.

  2013cited by this paper
• Identification of Thyroid Stimulating Hormone Receptor Inverse Agonists

  2013influential reference
• Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling.

  2013cited by this paper
• Research resource: novel structural insights bridge gaps in glycoprotein hormone receptor analyses.

  2013cited by this paper
• Inhibition of Follicle-Stimulating Hormone Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor 1 Running Title: FSHR Negative Allosteric Modulator

  2013cited by this paper
• Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid‐stimulating hormone receptor

  2012cited by this paper
• Update in TSH receptor agonists and antagonists.

  2012influential reference
• Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo.

  2012cited by this paper
• Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

  2012cited by this paper
• Regulatory processes governing the cell surface expression of LH and FSH receptors.

  2012cited by this paper
• The thyrotropin receptor hinge region as a surrogate ligand: identification of loci contributing to the coupling of thyrotropin binding and receptor activation.

  2012cited by this paper
• Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands.

  2012cited by this paper
• Complete inhibition of rhTSH-, Graves' disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist.

  2012cited by this paper
• Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling

  2011cited by this paper
• Chemogenomic Analysis of G-Protein Coupled Receptors and Their Ligands Deciphers Locks and Keys Governing Diverse Aspects of Signalling

  2011influential reference
• Regulatory T-cells in Graves' orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin.

  2011cited by this paper
• Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors?

  2011cited by this paper
• Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody.

  2011influential reference
• The dilemma of how to manage Graves' hyperthyroidism in patients with associated orbitopathy.

  2011cited by this paper
• Targeted biological therapies for Graves’ disease and thyroid‐associated ophthalmopathy. Focus on B‐cell depletion with Rituximab

  2011cited by this paper
• Crystal Structure of the β2Adrenergic Receptor-Gs protein complex

  2011cited by this paper
• Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist

  2011influential reference
• Defining Structural and Functional Dimensions of the Extracellular Thyrotropin Receptor Region*

  2011cited by this paper
• A novel mechanism involved in the pathogenesis of Graves ophthalmopathy (GO): clathrin is a possible targeting molecule for inhibiting local immune response in the orbit.

  2011cited by this paper
• A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor.

  2011cited by this paper
• Allosteric ligands for G protein‐coupled receptors: A novel strategy with attractive therapeutic opportunities

  2010cited by this paper
• Signaling by internalized G-protein-coupled receptors.

  2010cited by this paper
• Dominant negative effects of human follicle-stimulating hormone receptor expression-deficient mutants on wild-type receptor cell surface expression. Rescue of oligomerization-dependent defective receptor expression by using cognate decoys.

  2010cited by this paper
• Signaling‐sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor

  2010cited by this paper
• Principles and Determinants of G-Protein Coupling by the Rhodopsin-Like Thyrotropin Receptor

  2010cited by this paper
• A small molecule inverse agonist for the human thyroid-stimulating hormone receptor.

  2010cited by this paper
• Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor

  2010cited by this paper
• Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions.

  2009cited by this paper
• Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

  2009influential reference
• Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms.

  2009cited by this paper
• Current Insights into the Pathogenesis of Graves’ Orbitopathy

  2009cited by this paper
• Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine.

  2009cited by this paper
• The Role of Propylthiouracil in the Management of Graves' Disease in Adults: Report of a Meeting Jointly Sponsored by the American Thyroid Association and the Food and Drug Administration

  2009cited by this paper
• The thyroid-stimulating hormone receptor: impact of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on multimerization, cleavage, and signaling.

  2009cited by this paper
• A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism.

  2008influential reference
• Quantitative High-Throughput Screening Using a Live-Cell cAMP Assay Identifies Small-Molecule Agonists of the TSH Receptor

  2008influential reference

• Allosteric Regulators of the Thyroid-Stimulating Hormone Receptor: New Horizons in the Pharmacology of Thyroid Pathology

  2025influential citation
• The changing landscape of thyroid eye disease: current clinical advances and future outlook

  2024cites this paper
• Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor.

  2024cites this paper
• Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential.

  2024cites this paper
• A Review of Novel Medical Treatments for Thyroid Eye Disease

  2024cites this paper
• An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers.

  2024cites this paper
• Future Projections in Thyroid Eye Disease

  2022cites this paper
• Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction

  2022cites this paper
• Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes

  2021cites this paper
• Rescue of cell surface expression and signalling of mutant follicle-stimulating hormone receptors.

  2021cites this paper
• Modulating TSH Receptor Signaling for Therapeutic Benefit

  2020cites this paper
• Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

  2020cites this paper
• Rescue of Function of Mutant Luteinising Hormone Receptors with Deficiencies in Cell Surface Expression, Hormone Binding, and Hormone Signalling

  2020cites this paper
• Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

  2019cites this paper
• Hormone and Metabolic Research: 50 Years of Research

  2019cites this paper