Horm Metab Res 2018; 50(12): 894-907
DOI: 10.1055/a-0749-6528
Review
© Georg Thieme Verlag KG Stuttgart · New York

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

Gerd Krause
1   Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
,
Patrick Marcinkowski
1   Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
› Author Affiliations
Further Information

Publication History

received 16 July 2018

accepted 11 September 2018

Publication Date:
26 October 2018 (online)

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.

 
  • References

  • 1 Vassart G, Pardo L, Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 2004; 29: 119-126
  • 2 Manglik A, Kobilka BK, Steyaert J. Nanobodies to study G Protein–Coupled receptor structure and function. Annu Rev Pharmacol Toxicol 2017; 57: 19-37
  • 3 Wang W, Qiao Y, Li Z. New Insights into Modes of GPCR Activation. Trends Pharmacol Sci 2018; 1-20
  • 4 Flock T, Hauser AS, Lund N, Gloriam DE, Balaji S, Babu MM. Selectivity determinants of GPCR–G-protein binding. Nature 2017; 545: 317-322
  • 5 De Amici M, Dallanoce C, Holzgrabe U, Tränkle C, Mohr K. Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities. Med Res Rev 2010; 30: 463-549
  • 6 Congreve M, Oswald C, Marshall FH. Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Trends Pharmacol Sci 2017; 38: 837-847
  • 7 Gentry PR, Sexton PM, Christopoulos A. Novel Allosteric Modulators of G Protein-coupled Receptors. J Biol Chem 2015; 290: 19478-19488
  • 8 Thal DM, Glukhova A, Sexton PM, Christopoulos A. Structural insights into G-protein-coupled receptor allostery. Nature 2018; 559: 45-53
  • 9 Wacker D, Stevens RC, Roth BL. How Ligands Illuminate GPCR Molecular Pharmacology. Cell 2017; 170: 414-427
  • 10 Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Madan Babu M. Molecular signatures of G-protein-coupled receptors. Nature 2013; 494: 185-194
  • 11 Liu X, Ahn S, Kahsai AW, Meng K-C, Latorraca NR, Pani B, Venkatakrishnan AJ, Masoudi A, Weis WI, Dror RO, Chen X, Lefkowitz RJ, Kobilka BK. Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature 2017; 548: 480-484
  • 12 Zhang D, Gao Z-G, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W, Han GW, Liu H, Cherezov V, Katritch V, Jiang H, Stevens RC, Jacobson KA, Zhao Q, Wu B. Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 2015; 520: 317-321
  • 13 Cooke RM, Brown AJH, Marshall FH, Mason JS. Structures of G protein-coupled receptors reveal new opportunities for drug discovery. Drug Discov Today 2015; 20: 1355-1364
  • 14 Munk C, Harpsøe K, Hauser AS, Isberg V, Gloriam DE. Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol 2016; 30: 51-58
  • 15 Stenkamp RE. Identifying G protein-coupled receptor dimers from crystal packings. Acta Crystallogr Sect D 2018; 74: 655-670
  • 16 Casadó-Anguera V, Bonaventura J, Moreno E, Navarro G, Cortés A, Ferré S, Casadó V. Evidence for the heterotetrameric structure of the adenosine A2A-dopamine D2 receptor complex. Biochem Soc Trans 2016; 44: 595-600
  • 17 Meral D, Provasi D, Prada-Gracia D, Möller J, Marino K, Lohse MJ, Filizola M. Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations. Sci Rep 2018; 8: 7705
  • 18 Kleinau G, Mueller S, Jaeschke H, Grzesik P, Neumann S, Diehl A, Paschke R, Krause G. Defining structural and functional dimensions of the extracellular thyrotropin receptor region. J Biol Chem 2011; 286: 22622-22631
  • 19 Kleinau G, Krause G. Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr Rev 2009; 30: 133-151
  • 20 Kleinau G, Neumann S, Grüters A, Krude H, Biebermann H. Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 2013; 34: 691-724
  • 21 Zhang M, Tong KPT, Fremont V, Chen J, Narayan P, Puett D, Weintraub BD, Szkudlinski MW. The extracellular domain suppresses constitutive activity of the transmembrane domain of the human TSH receptor: Implications for hormone-receptor interaction and antagonist design. Endocrinology 2000; 141: 3514-3517
  • 22 Zhang ML, Sugawa H, Kosugi S, Mori T. Constitutive activation of the thyrotropin receptor by deletion of a portion of the extracellular domain. Biochem Biophys Res Commun 1995; 211: 205-210
  • 23 Vlaeminck-Guillem V, Ho S-C, Rodien P, Vassart G, Costagliola S. Activation of the cAMP pathway by the TSH receptor involves switching of the ectodomain from a tethered inverse agonist to an agonist. Mol Endocrinol 2002; 16: 736-746
  • 24 Alvarez CA, Narayan P, Huang J, Puett D. Characterization of a Region of the Lutropin Receptor Extracellular Domain Near Transmembrane Helix 1 That Is Important in Ligand-Mediated Signaling. Endocrinology 1999; 140: 1775-1782
  • 25 Kleinau G, Jäschke H, Neumann S, Lättig J, Paschke R, Krause G. Identification of a novel epitope in the thyroid-stimulating hormone receptor ectodomain acting as intramolecular signaling interface. J Biol Chem 2004; 279: 51590-51600
  • 26 Mueller S, Kleinau G, Jaeschke H, Neumann S, Krause G, Paschke R. Significance of ectodomain cysteine boxes 2 and 3 for the activation mechanism of the thyroid-stimulating hormone receptor. J Biol Chem 2006; 281: 31638-31646
  • 27 Chen CR, Salazar LM, McLachlan SM, Rapoport B. The thyrotropin receptor hinge region as a surrogate ligand: Identification of loci contributing to the coupling of thyrotropin binding and receptor activation. Endocrinology 2012; 153: 5058-5067
  • 28 Brüser A, Schulz A, Rothemund S, Ricken A, Calebiro D, Kleinau G, Schöneberg T. The activation mechanism of glycoprotein hormone receptors with implications in the cause and therapy of endocrine diseases. J Biol Chem 2016; 291: 508-520
  • 29 Kleinau G, Worth CL, Kreuchwig A, Biebermann H, Marcinkowski P, Scheerer P, Krause G. Structural-functional features of the thyrotropin receptor: A class A G-protein-coupled receptor at work. Front Endocrinol (Lausanne) 2017; 8: 86
  • 30 Neumann S, Huang W, Titus S, Krause G, Kleinau G, Alberobello AT, Zheng W, Southall NT, Inglese J, Austin CP, Celi FS, Gavrilova O, Thomas CJ, Raaka BM, Gershengorn MC. Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc Natl Acad Sci U S A 2009; 106: 12471-12476
  • 31 Nataraja S, Sriraman V, Palmer S. Allosteric Regulation of the Follicle-Stimulating Hormone Receptor. Endocrinology 2018; 159: 2704-2716
  • 32 Kleinau G, Jaeschke H, Worth CL, Mueller S, Gonzalez J, Paschke R, Krause G. Principles and Determinants of G-Protein Coupling by the Rhodopsin-Like Thyrotropin Receptor. PLoS One 2010; 5: e9745
  • 33 Reiter E, Ayoub MA, Pellissier LP, Landomiel F, Musnier A, Tréfier A, Gandia J, De Pascali F, Tahir S, Yvinec R, Bruneau G, Poupon A, Crépieux P. β-arrestin signalling and bias in hormone-responsive GPCRs. Mol Cell Endocrinol 2017; 449: 28-41
  • 34 Latorraca NR, Wang JK, Bauer B, Townshend RJL, Hollingsworth SA, Olivieri JE, Xu HE, Sommer ME, Dror RO. Molecular mechanism of GPCR-mediated arrestin activation. Nature 2018; 557: 452-456
  • 35 Dias JA, Cohen BD, Lindau-Shepard B, Nechamen CA, Peterson AJ, Schmidt A. Molecular, structural, and cellular biology of follitropin and follitropin receptor. Vitam Horm 2002; 64: 249-322
  • 36 Farid NR, Kascur V, Balazs C. The human thyrotropin receptor is highly mutable: A review of gain-of-function mutations. Eur J Endocrinol 2000; 143: 25-30
  • 37 Latif R, Morshed SA, Zaidi M, Davies TF. The Thyroid-Stimulating Hormone Receptor: Impact of Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Antibodies on Multimerization, Cleavage, and Signaling. Endocrinol Metab Clin North Am 2009; 38: 319-341
  • 38 Puett D, Li Y, Angelova K, Demars G, Meehan TP, Fanelli F, Narayan P. Structure-function relationships of the luteinizing hormone receptor. Ann N Y Acad Sci 2005; 1061: 41-54
  • 39 Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 1998; 19: 673-716
  • 40 Urizar E, Montanelli L, Loy T, Bonomi M, Swillens S, Gales C, Bouvier M, Smits G, Vassart G, Costagliola S. Glycoprotein hormone receptors: Link between receptor homodimerization and negative cooperativity. EMBO J 2005; 24: 1954-1964
  • 41 Kreuchwig A, Kleinau G, Krause G. Research Resource: Novel Structural Insights Bridge Gaps in Glycoprotein Hormone Receptor Analyses. Mol Endocrinol 2013; 27: 1357-1363
  • 42 Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 2017; 16: 829-842
  • 43 Calebiro D, de Filippis T, Lucchi S, Covino C, Panigone S, Beck-Peccoz P, Dunlap D, Persani L. Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Hum Mol Genet 2005; 14: 2991-3002
  • 44 Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 2005; 433: 269-277
  • 45 Fan QR, Hendrickson WA. Assembly and structural characterization of an authentic complex between human follicle stimulating hormone and a hormone-binding ectodomain of its receptor. Mol Cell Endocrinol 2007; 260–262: 73-82
  • 46 Jiang X, Liu H, Chen X, Chen P-H, Fischer D, Sriraman V, Yu HN, Arkinstall S, He X. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci USA 2012; 109: 12491-12496
  • 47 Sanders J, Chirgadze DY, Sanders P, Baker S, Sullivan A, Bhardwaja A, Bolton J, Reeve M, Nakatake N, Evans M, Richards T, Powell M, Miguel RN, Blundell TL, Furmaniak J, Smith BR. Crystal Structure of the TSH Receptor in Complex with a Thyroid-Stimulating Autoantibody. Thyroid 2007; 17: 395-410
  • 48 Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Miguel RN, Furmaniak J, Smith BR, Núñez Miguel R, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 2011; 46: 81-99
  • 49 Worth CL, Kreuchwig F, Tiemann JKS, Kreuchwig A, Ritschel M, Kleinau G, Hildebrand PW, Krause G. GPCR-SSFE 2.0 - A fragment-based molecular modeling web tool for Class A G-protein coupled receptors. Nucleic Acids Res 2017; 45: W408-W415
  • 50 Manglik A, Kruse AC. Structural Basis for G Protein-Coupled Receptor Activation. Biochemistry 2017; 56: 5628-5634
  • 51 Jiang X, Fischer D, Chen X, McKenna SD, Liu H, Sriraman V, Yu HN, Goutopoulos A, Arkinstall S, He X. Evidence for follicle-stimulating hormone receptor as a functional trimer. J Biol Chem 2014; 289: 14273-14282
  • 52 Vassart G, Kleinau G. TSH Receptor Mutations and Diseases. South Dartmouth (MA): Endotext; 2014
  • 53 Schaarschmidt J, Nagel MBM, Huth S, Jaeschke H, Moretti R, Hintze V, Von Bergen M, Kalkhof S, Meiler J, Paschke R. Rearrangement of the extracellular domain/extracellular loop 1 interface is critical for thyrotropin receptor activation. J Biol Chem 2016; 291: 14095-14108
  • 54 Puett D, Li Y, DeMars G, Angelova K, Fanelli F. A functional transmembrane complex: the luteinizing hormone receptor with bound ligand and G protein. Mol Cell Endocrinol 2007; 260–262: 126-136
  • 55 Ulloa-Aguirre A, Zarinan T. The Follitropin Receptor: Matching Structure and Function. Mol Pharmacol 2016; 90: 596-608
  • 56 Bonomi M, Persani L. Modern methods to investigate the oligomerization of glycoprotein hormone receptors (TSHR, LHR, FSHR). Methods Enzymol 2013; 521: 367-383
  • 57 Mazurkiewicz JE, Herrick-Davis K, Barroso M, Ulloa-Aguirre A, Lindau-Shepard B, Thomas RM, Dias JA. Single-Molecule Analyses of Fully Functional Fluorescent Protein-Tagged Follitropin Receptor Reveal Homodimerization and Specific Heterodimerization with Lutropin Receptor1. Biol Reprod 2015; 92: 100
  • 58 Feng X, Zhang M, Guan R, Segaloff DL. Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling. Endocrinology 2013; 154: 3925-3930
  • 59 Segaloff DL. Regulatory processes governing the cell surface expression of LH and FSH receptors. Subcell Biochem 2012; 63: 113-129
  • 60 Rivero-Müller A, Jonas KC, Hanyaloglu AC, Huhtaniemi I. Di/oligomerization of GPCRs-mechanisms and functional significance. Prog Mol Biol Transl Sci 2013; 117: 163-185
  • 61 Grzesik P, Kreuchwig A, Rutz C, Furkert J, Wiesner B, Schuelein R, Kleinau G, Gromoll J, Krause G. Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor’s Extracellular Hinge Region. Front Endocrinol (Lausanne) 2015; 6: 140
  • 62 Jonas KC, Fanelli F, Huhtaniemi IT, Hanyaloglu AC. Single Molecule Analysis of Functionally Asymmetric G Protein-coupled Receptor (GPCR) Oligomers Reveals Diverse Spatial and Structural Assemblies. J Biol Chem 2015; 290: 3875-3892
  • 63 Yanofsky SD, Shen ES, Holden F, Whitehorn E, Aguilar B, Tate E, Holmes CP, Scheuerman R, MacLean D, Wu MM, Frail DE, López FJ, Winneker R, Arey BJ, Barrett RW. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. J Biol Chem 2006; 281: 13226-13233
  • 64 Sanders J, Bolton J, Sanders P, Jeffreys J, Nakatake N, Richards T, Evans M, Kiddie A, Summerhayes S, Roberts E, Miguel RN, Furmaniak J, Smith BR. Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH. Thyroid 2006; 16: 1195-1206
  • 65 Allen MD, Neumann S, Gershengorn MC. Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling. FASEB J 2011; 25: 3687-3694
  • 66 Troppmann B, Kleinau G, Krause G, Gromoll J. Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor. Hum Reprod Update 2013; 19: 583-602
  • 67 Leidenheimer NJ, Ryder KG. Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol Res 2014; 83: 10-19
  • 68 Zariñán T, Perez-Solís MA, Maya-Núñez G, Casas-González P, Conn PM, Dias JA, Ulloa-Aguirre A. 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. Mol Cell Endocrinol 2010; 321: 112-122
  • 69 Newton CL, Whay AM, McArdle CA, Zhang M, van Koppen CJ, van de Lagemaat R, Segaloff DL, Millar RP. Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci USA 2011; 108: 7172-7176
  • 70 Newton CL, Anderson RC. Pharmacoperones for Misfolded Gonadotropin Receptors. Handb Exp Pharmacol 2018; 245: 111-134
  • 71 Janovick JA, Maya-Núñez G, Ulloa-Aguirre A, Huhtaniemi IT, Dias JA, Verbost P, Conn PM. Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine. Mol Cell Endocrinol 2009; 298: 84-88
  • 72 Nataraja SG, Yu HN, Palmer SS. Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors. Front Endocrinol (Lausanne) 2015; 6: 142
  • 73 De Pascali F, Tréfier A, Landomiel F, Bozon V, Bruneau G, Yvinec R, Poupon A, Crépieux P, Reiter E. Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges. Int Rev Cell Mol Biol 2018; 338: 1-58
  • 74 Heitman LH, Kleinau G, Brussee J, Krause G, Ijzerman AP. Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands. Mol Cell Endocrinol 2012; 351: 326-336
  • 75 Jorand-Lebrun C, Brondyk B, Lin J, Magar S, Murray R, Reddy A, Shroff H, Wands G, Weiser W, Xu Q, McKenna S, Brugger N. Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists. Bioorg Med Chem Lett 2007; 17: 2080-2085
  • 76 Van Koppen CJ, Zaman GJR, Timmers CM, Kelder J, Mosselman S, Van De Lagemaat R, Smit MJ, Hanssen RGJM. A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor. Naunyn Schmiedebergs Arch Pharmacol 2008; 378: 503-514
  • 77 Arey BJ. Allosteric modulators of glycoprotein hormone receptors: Discovery and therapeutic potential. Endocrine 2008; 34: 1-10
  • 78 Van Straten NCR, Van Berkel THJ, Demont DR, Karstens WJF, Merkx R, Oosterom J, Schulz J, Van Someren RG, Timmers CM, Van Zandvoort PM. Identification of substituted 6-amino-4-phenyltetrahydroquinoline derivatives: Potent antagonists for the follicle-stimulating hormone receptor. J Med Chem 2005; 48: 1697-1700
  • 79 Dias JA, Bonnet B, Weaver BA, Watts J, Kluetzman K, Thomas RM, Poli S, Mutel V, Campo B. A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor. Mol Cell Endocrinol 2011; 333: 143-150
  • 80 Dias JA, Campo B, Weaver BA, Watts J, Kluetzman K, Thomas RM, Bonnet B, Mutel V, Poli SM. Inhibition of follicle-stimulating hormone-induced preovulatory follicles in rats treated with a nonsteroidal negative allosteric modulator of follicle-stimulating hormone receptor. Biol Reprod 2014; 90: 19
  • 81 Ayoub MA, Yvinec R, Jégot G, Dias JA, Poli SM, Poupon A, Crépieux P, Reiter E. Profiling of FSHR negative allosteric modulators on LH/CGR reveals biased antagonism with implications in steroidogenesis. Mol Cell Endocrinol 2016; 436: 10-22
  • 82 Van Straten NCR, Schoonus-Gerritsma GG, Van Someren RG, Draaijer J, Adang AEP, Timmers CM, Hanssen RGJM, Van Boeckel CAA. The first orally active low molecular weight agonists for the LH receptor: Thienopyr(im)idines with therapeutic potential for ovulation induction. ChemBioChem 2002; 3: 1023-1026
  • 83 Moore S, Jaeschke H, Kleinau G, Neumann S, Costanzi S, Jiang JK, Childress J, Raaka BM, Colson A, Paschke R, Krause G, Thomas CJ, Gershengorn MC. Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: Structure-activity relationships and selective binding patterns. J Med Chem 2006; 49: 3888-3896
  • 84 Endo T, Kobayashi T. Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo. Am J Physiol Endocrinol Metab 2012; 302: E1569-E1575
  • 85 Laugwitz K-L, Allgeiertt A, Offermanns S, Spicher K, Van Sandet J, Dumontt JE, Schultz G, Bourne HR. The human thyrotropin receptor: A heptahelical receptor capable of stimulating members of all four G protein families. Cell Biol 1996; 93: 116-120
  • 86 Kero J, Ahmed K, Wettschureck N, Tunaru S, Wintermantel T, Greiner E, Schütz G, Offermanns S. Thyrocyte-specific G q / G 11 deficiency impairs thyroid function and prevents goiter development. J Clin Invest 2007; 117: 2399-2407
  • 87 Boutin A, Eliseeva E, Gershengorn MC, Neumann S. β-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J 2014; 28: 3446-3455
  • 88 Rapoport B, McLachlan SM. TSH receptor cleavage into subunits and shedding of the A-subunit; a molecular and clinical perspective. Endocr Rev 2016; 37: 114-134
  • 89 Davies TF, Latif R. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies. Expert Opin Ther Targets 2015; 19: 835-847
  • 90 Núñez Miguel R, Sanders J, Chirgadze DY, Furmaniak J, Rees Smith B. Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: A comparative structural study of protein-protein interactions. J Mol Endocrinol 2009; 42: 381-395
  • 91 Furmaniak J, Sanders J, Núñez Miguel R, Rees Smith B. Mechanisms of Action of TSHR Autoantibodies. Horm Metab Res 2015; 47: 735-752
  • 92 Ferraz C, Paschke R. Inheritable and sporadic non-autoimmune hyperthyroidism. Best Pract Res Clin Endocrinol Metab 2017; 31: 265-275
  • 93 Bahn RS. Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Thyroid 2002; 12: 193-195
  • 94 Meyer Zu Hörste M, Ströher E, Berchner-Pfannschmidt U, Schmitz-Spanke S, Pink M, Göthert JR, Fischer JW, Gulbins E, Eckstein AK. 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. J Clin Endocrinol Metab 2011; 96: E1727-E1736
  • 95 Wiersinga WM. Autoimmunity in Graves’ ophthalmopathy: The result of an unfortunate marriage between TSH receptors and IGF-1 receptors?. J Clin Endocrinol Metab 2011; 96: 2386-2394
  • 96 Sato S, Noh JY, Sato S, Suzuki M, Yasuda S, Matsumoto M, Kunii Y, Mukasa K, Sugino K, Ito K, Nagataki S, Taniyama M. 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. Thyroid 2015; 25: 43-50
  • 97 Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN. 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. Thyroid 2009; 19: 673-674
  • 98 Meyer Zu Horste M, Pateronis K, Walz MK, Alesina P, Mann K, Schott M, Esser J, Eckstein AK. The effect of early thyroidectomy on the course of active Graves’ Orbitopathy (GO): A retrospective case study. Horm Metab Res 2016; 48: 433-439
  • 99 Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995; 42: 45-50
  • 100 Eckstein AK, Johnson KTM, Thanos M, Esser J, Ludgate M. Current insights into the pathogenesis of Graves’ orbitopathy. Horm Metab Res 2009; 41: 456-464
  • 101 Bartalena L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab 2011; 96: 592-599
  • 102 Calebiro D, Nikolaev VO, Persani L, Lohse MJ. Signaling by internalized G-protein-coupled receptors. Trends Pharmacol Sci 2010; 31: 221-228
  • 103 Kahaly GJ, Shimony O, Gellman YN, Lytton SD, Eshkar-Sebban L, Rosenblum N, Refaeli E, Kassem S, Ilany J, Naor D. Regulatory T-cells in Graves’ orbitopathy: Baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Metab 2011; 96: 422-429
  • 104 Hegedüs L, Smith TJ, Douglas RS, Nielsen CH. Targeted biological therapies for Graves’ disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab. Clin Endocrinol (Oxf) 2011; 74: 1-8
  • 105 Burton BR, Britton GJ, Fang H, Verhagen J, Smithers B, Sabatos-Peyton CA, Carney LJ, Gough J, Strobel S, Wraith DC. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat Commun 2014; 5: 4741
  • 106 Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med 2017; 376: 1748-1761
  • 107 Chen H, Shan SJC, Mester T, Wei Y-H, Douglas RS. TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist. PLoS One 2015; 10: e0130322
  • 108 Neumann S, Place RF, Krieger CC, Gershengorn MC. Future Prospects for the Treatment of Graves’ Hyperthyroidism and Eye Disease. Horm Metab Res 2015; 47: 789-796
  • 109 Gershengorn MC, Neumann S. Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 2012; 97: 4287-4292
  • 110 Rossi M, Dimida A, Dell’anno MT, Trincavelli ML, Agretti P, Giorgi F, Corsini GU, Pinchera A, Vitti P, Tonacchera M, Maggio R. The thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane appears to be an uncompetitive inverse agonist for the thyrotropin receptor. J Pharmacol Exp Ther 2007; 320: 465-474
  • 111 Neumann S, Kleinau G, Costanzi S, Moore S, Jiang J, Raaka BM, Thomas CJ, Krause G, Gershengorn MC. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology 2008; 149: 5945-5950
  • 112 Neumann S, Huang W, Eliseeva E, Titus S, Thomas CJ, Gershengorn MC. A small molecule inverse agonist for the human thyroid-stimulating hormone receptor. Endocrinology 2010; 151: 3454-3459
  • 113 Huang W, Englund E, Titus S, Southall N, Zheng W, Ferrer M, Marugan J, Neumann S, Gershengorn M. Identification of thyroid stimulating hormone receptor inverse agonists. Probe Reports from NIH Mol Libr Progr 2010; 1-30
  • 114 Turcu AF, Kumar S, Neumann S, Coenen M, Iyer S, Chiriboga P, Gershengorn MC, Bahn RS. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of graves ophthalmopathy. J Clin Endocrinol Metab 2013; 98: 2153-2159
  • 115 Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC. A Selective TSH Receptor Antagonist Inhibits Stimulation of Thyroid Function in Female Mice. Endocrinology 2014; 155: 310-314
  • 116 Krieger CC, Place RF, Bevilacqua C, Marcus-Samuels B, Abel BS, Skarulis MC, Kahaly GJ, Neumann S, Gershengorn MC. TSH/IGF-1 receptor cross talk in graves’ ophthalmopathy pathogenesis. J Clin Endocrinol Metab 2016; 101: 2340-2347
  • 117 Krieger CC, Neumann S, Marcus-Samuels B, Gershengorn MC. TSHR/IGF-1R Cross-Talk, Not IGF-1R Stimulating Antibodies, Mediates Graves’ Ophthalmopathy Pathogenesis. Thyroid 2017; 27: 746-747
  • 118 Marcus-Samuels B, Krieger CC, Boutin A, Kahaly GJ, Neumann S, Gershengorn MC. Evidence That Graves’ Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors. Thyroid 2018; 28: 650-655
  • 119 Van Koppen CJ, De Gooyer ME, Karstens WJ, Plate R, Conti PGM, Van Achterberg TAE, Van Amstel MGA, Brands JHGM, Wat J, Berg RJW, Lane JRD, Miltenburg AMM, Timmers CM. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor. Br J Pharmacol 2012; 165: 2314-2324
  • 120 Van Zeijl CJJ, Van Koppen CJ, Surovtseva OV, De Gooyer ME, Plate R, Conti P, Karstens WJ, Timmers M, Saeed P, Wiersinga WM, Miltenburg AMM, Fliers E, Boelen A. Complete inhibition of rhTSH-, Graves’ disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist. J Clin Endocrinol Metab 2012; 97: E781-E785
  • 121 Latif R, Realubit RB, Karan C, Mezei M, Davies TF. TSH Receptor Signaling Abrogation by a Novel Small Molecule. Front Endocrinol (Lausanne) 2016; 7: 130
  • 122 Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, Sobottka S, Sun H, Nazare M, Berchner-Pfannschmidt U, von Kries JP, Eckstein A, Schülein R, Krause G. A new highly thyrotropin receptor-selective small molecule antagonist with potential for the therapy of Graves’ orbitopathy. Thyroid 2018 in press
  • 123 Neumann S, Padia U, Cullen MJ, Eliseeva E, Nir EA, Place RF, Morgan SJ, Gershengorn MC. An enantiomer of an oral small-molecule TSH receptor agonist exhibits improved pharmacologic properties. Front Endocrinol (Lausanne) 2016; 7: 4-11
  • 124 Jäschke H, Neumann S, Moore S, Thomas CJ, Colson AO, Costanzi S, Kleinau G, Jiang JK, Paschke R, Raaka BM, Krause G, Gershengorn MC. A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem 2006; 281: 9841-9844
  • 125 Kleinau G, Haas A-K, Neumann S, Worth CL, Hoyer I, Furkert J, Rutz C, Gershengorn MC, Schulein R, Krause G. Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor. FASEB J 2010; 24: 2347-2354
  • 126 Haas A-KK, Kleinau G, Hoyer I, Neumann S, Furkert J, Rutz C, Schülein R, Gershengorn MC, Krause G. Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor. Cell Mol Life Sci 2011; 68: 159-167
  • 127 Hoyer I, Haas A-K, Kreuchwig A, Schülein R, Krause G. Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists. Biochem Soc Trans 2013; 41: 213-217
  • 128 Titus S, Neumann S, Zheng W, Southall N, Michael S, Klumpp C, Yasgar A, Shinn P, Thomas CJ, Inglese J, Gershengorn MC, Austin CP. Quantitative high-throughput screening using a live-cell cAMP assay identifies small-molecule agonists of the TSH receptor. J Biomol Screen 2008; 13: 120-127
  • 129 Neumann S, Eliseeva E, Boutin A, Barnaeva E, Ferrer M, Southall N, Kim D, Hu X, Morgan SJ, Marugan JJ, Gershengorn MC. Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro. J Pharmacol Exp Ther 2018; 364: 38-45
  • 130 Latif R, Ali MR, Ma R, David M, Morshed SA, Ohlmeyer M, Felsenfeld DP, Lau Z, Mezei M, Davies TF. New Small Molecule Agonists to the Thyrotropin Receptor. Thyroid 2015; 25: 51-62
  • 131 Wichard JD, Ter Laak A, Krause G, Heinrich N, Kühne R, Kleinau G. Chemogenomic analysis of G-protein coupled receptors and their ligands deciphers locks and keys governing diverse aspects of signalling. PLoS One 2011; 6: e16811
  • 132 Rasmussen SGF, Devree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah STA, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK. Crystal structure of the β 2 adrenergic receptor-Gs protein complex. Nature 2011; 477: 549-557