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

Krause, Gerd; Marcinkowski, Patrick

doi:10.1055/a-0749-6528

Cited by 14 publications

(13 citation statements)

References 129 publications

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“…CH and the internal agonist sequences are both embedded in between the ECLs of the seven TMH [reviewed in and Krause and Marcinkowski (2018)]. According to our own and other molecular models of TSHR (Kleinau and Vassart, 2017), CH interacts with ECL1, as is also supported by the strong CAM of S281Q (located at CH) and I486F (located at ECL1) (Fig.…”

Section: Course Of Intramolecular Activation Mechanism At the Ecd/tmdmentioning

confidence: 74%

“…Antithyroid drugs available on the market inhibit thyroid hormone synthesis in the thyroid gland but do not act directly on the TSHR and are therefore less effective in the treatment of GO (Sato et al, 2015). Small molecules acting directly on the TSHR are thought to interact allosterically in the transmembrane domain (TMD) as positive and negative allosteric modulators [(PAM, NAM), reviewed in Krause and Marcinkowski (2018)].…”

Section: Introductionmentioning

confidence: 99%

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Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

et al. 2019

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The large TSH-bound ectodomain of the thyrotropin receptor (TSHR) activates the transmembrane domain (TMD) indirectly via an internal agonist (IA). The ectodomain/TMD interface consists of a converging helix, a Cys-Cys-bridge-linked IA, and extracellular loops (ECL). To investigate the intramolecular course of molecular activation, especially details of the indirect activation, we narrowed down allosteric inhibition sites of negative allosteric modulator (NAM) by mutagenesis, homology modeling, and competition studies with positive allosteric modulator (PAM). From the inhibitory effects of NAM S37a on: 1) chimeras with swapped ectodomain, 2) stepwise N-terminal truncations, 3) distinct constitutively active mutations distributed across the hinge region and ECL, but not across the TMD, we conclude that S37a binds at the ectodomain/TMD interface, between the converging helix, ECL1, and the IA. This is also supported by the noncompetitive inhibition of PAM-C2-activation by S37a in the TSHR-TMD construct lacking the ectodomain. Mutagenesis studies on the IA and ECL were guided by our refined model of the ectodomain/TMD interface and indicate an interaction with the TSHR-specific residues E404 (preceding IA) and H478 (ECL1). At this new allosteric interaction site, NAM S37a blocks both TSH-and PAM-induced activation of the TSHR. Our refined models, mutations, and new allosteric binding pocket helped us to gain more detailed insights into the intramolecular course of TSHR activation at the ectodomain/TMD interface, including the delocalization of the converging helix and rearrangement of the conformation of IA. These changes are embedded between the ECL and cooperatively trigger active conformations of TMD. SIGNIFICANCE STATEMENT The intramolecular activation mechanisms of the TSHR appear to be distinct from those of other G protein-coupled receptors, as the TSHR has a uniquely large N-terminal ectodomain that includes the hormone binding site and an internal agonist sequence. We present new molecular and structural insights into the interface between ectodomain and transmembrane domain in the TSHR, as well as the transfer of activation to the transmembrane domain. This knowledge is critical for understanding activation or inhibition of the receptor by allosteric ligands. We have identified a new allosteric antagonist binding pocket that is located exactly at this interface and possesses specific features that may allow the generation of potent highly TSHR-selective drugs, of potential value for the treatment of Graves' orbitopathy.

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Section: Course Of Intramolecular Activation Mechanism At the Ecd/tmdmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

et al. 2019

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“…An important advantage of these small organic molecule TSHR antagonists is their oral availability that would allow easier administration outside the clinic compared to antibodies that must be administered parenterally. Small molecule TSHR antagonists have been extensively reviewed recently [39], and therefore, we will focus on selected compounds. Latif et al [37] developed an indole-thiazole derivative named VA-K-14.…”

Section: Tshr-targeted Treatmentsmentioning

confidence: 99%

Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

Neumann¹,

Krieger²,

Gershengorn³

2020

Eur Thyroid J

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Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.

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“…Most recently, we also focused on thyroid diseases, e. g. autoimmune thyroid disease; here another three special issues were published highlighting the genetic cause as well as the immunological background, diagnostic procedures and therapeutic options in Graves' disease and autoimmune thyroiditis, including a most recent special issue [16][17][18][19][20][21][22][23][24].…”

Section: Dear Readersmentioning

confidence: 99%