{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:37:53Z","timestamp":1784673473392,"version":"3.55.0"},"reference-count":68,"publisher":"Bioscientifica","issue":"6","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["etj.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,20]]},"abstract":"<jats:p>Cryo-EM studies indicate that full-length human TSH receptor (TSHR) is a monomer consisting of a leucine-rich repeat (LRR) domain (LRD), hinge region (HR) and transmembrane domain (TMD). Receptor autoantibodies (TRAb) bind to the extracellular domain (LRD plus HR). In the cell membrane, TSHR transitions between inactive and active states, involving rotation of the LRD about the HR, with the active state LRD further from the membrane. Cryo-EM structures of the TSHR in complex with different human monoclonal autoantibodies provide a detailed understanding of how they interact with the receptor. Stimulating monoclonal autoantibody M22\u2122 binds to the entire LRD (LRR 1\u201311) concave surface and cannot interact with the inactive state receptor, as this would result in a clash between antibody and membrane. No clash occurs when M22\u2122 binds the active state, and once bound, M22\u2122 holds the receptor in the active state, resulting in prolonged activation. K1-18\u2122, a different stimulating monoclonal autoantibody, interacts with LRR 1\u201311 in a similar way to M22\u2122. Blocking type monoclonal autoantibody K1-70\u2122 only interacts with LRR 1\u20137, positioning itself clear of the cell membrane when interacting with inactive or active receptor states. Once bound, binding of TSH and other TRAb is prevented. Monoclonal autoantibody 5C9\u2122 interacts differently, binding the inactive conformation from LRR 3 to the HR. Its heavy chain CDR3 interacts with the HR, locking the receptor in the inactive state, causing inhibition of constitutive activity, activating mutation activity and blocking receptor binding by TSH and TRAb. Elucidation of the structure of the TSHR and mechanisms of its activation and inactivation by TRAb is of great importance for the development of new TSHR-specific drugs.<\/jats:p>","DOI":"10.1530\/etj-25-0261","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T11:39:21Z","timestamp":1763638761000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-16","source":"Crossref","is-referenced-by-count":1,"title":["The thyrotropin receptor structure and interactions with autoantibodies"],"prefix":"10.1530","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9789-2484","authenticated-orcid":true,"given":"Bernard","family":"Rees Smith","sequence":"first","affiliation":[{"name":"FIRS Laboratories, RSR Ltd, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"N\u00fa\u00f1ez Miguel","sequence":"additional","affiliation":[{"name":"FIRS Laboratories, RSR Ltd, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Sanders","sequence":"additional","affiliation":[{"name":"FIRS Laboratories, RSR Ltd, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"J Mol Endocrinol","article-title":"Structure of full-length TSH receptor in complex with antibody K1-70\u2122","volume":"70","author":"N\u00fa\u00f1ez MR","year":"2022","unstructured":"N\u00fa\u00f1ez MR\n, \nSanders P\n, \nAllen L\n, et al.\n Structure of full-length TSH receptor in complex with antibody K1-70\u2122. J Mol Endocrinol 2022 70 e220120. (https:\/\/doi.org\/10.1530\/JME-22-0120)"},{"key":"bib2","series-title":"Endocr Rev","first-page":"106","article-title":"Autoantibodies to the thyrotropin receptor","volume":"9","author":"Rees Smith B","year":"1988","unstructured":"Rees Smith B\n, \nMcLachlan SM\n & \nFurmaniak J\n\n. Autoantibodies to the thyrotropin receptor. Endocr Rev 1988 9 106\u2013121. (https:\/\/doi.org\/10.1210\/edrv-9-1-106)"},{"key":"bib3","series-title":"J Clin Endocrinol Metab","first-page":"734","article-title":"Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves\u2019 disease and Hashimoto\u2019s thyroiditis","volume":"46","author":"Endo K","year":"1978","unstructured":"Endo K\n, \nKasagi K\n, \nKonishi J\n, et al.\n Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves\u2019 disease and Hashimoto\u2019s thyroiditis. J Clin Endocrinol Metab 1978 46 734\u2013739. (https:\/\/doi.org\/10.1210\/jcem-46-5-734)"},{"key":"bib4","series-title":"Clin Endocrinol","first-page":"207","article-title":"Thyroid-stimulating immunoglobulins in ophthalmic Graves\u2019 disease","volume":"6","author":"Teng CS","year":"1977","unstructured":"Teng CS\n, \nSmith BR\n, \nClayton B\n, et al.\n Thyroid-stimulating immunoglobulins in ophthalmic Graves\u2019 disease. Clin Endocrinol 1977 6 207\u2013211. (https:\/\/doi.org\/10.1111\/j.1365-2265.1977.tb03316.x)"},{"key":"bib5","series-title":"Clin Endocrinol","first-page":"404","article-title":"Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample","volume":"73","author":"Evans M","year":"2010","unstructured":"Evans M\n, \nSanders J\n, \nTagami T\n, et al.\n Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrinol 2010 73 404\u2013412. (https:\/\/doi.org\/10.1111\/j.1365-2265.2010.03831.x)"},{"key":"bib6","series-title":"J Thyroid Res","article-title":"Changes of TSH-stimulation blocking antibody (TSBAb) and thyroid stimulating antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive patients with hyperthyroidism: re-evaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients","volume":"2012","author":"Takasu N","year":"2012","unstructured":"Takasu N\n, \nKonishi J\n, \nLida Y\n, et al.\n Changes of TSH-stimulation blocking antibody (TSBAb) and thyroid stimulating antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive patients with hyperthyroidism: re-evaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients. J Thyroid Res 2012 2012 182176. (https:\/\/doi.org\/10.1155\/2012\/182176)"},{"key":"bib7","series-title":"Clin Endocrinol","first-page":"369","article-title":"Thyrotropin receptor antibody concentration and activity, several years after treatment for Graves\u2019 disease","volume":"90","author":"Nalla P","year":"2019","unstructured":"Nalla P\n, \nYoung S\n, \nSanders J\n, et al.\n Thyrotropin receptor antibody concentration and activity, several years after treatment for Graves\u2019 disease. Clin Endocrinol 2019 90 369\u2013374. (https:\/\/doi.org\/10.1111\/cen.13908)"},{"key":"bib8","series-title":"Clin Endocrinol","first-page":"465","article-title":"Thyrotropin receptor antibody characteristics in a woman with long-standing Hashimoto\u2019s who developed Graves\u2019 disease and pretibial myxoedema","volume":"77","author":"Kamath C","year":"2012","unstructured":"Kamath C\n, \nYoung S\n, \nKabelis K\n, et al.\n Thyrotropin receptor antibody characteristics in a woman with long-standing Hashimoto\u2019s who developed Graves\u2019 disease and pretibial myxoedema. Clin Endocrinol 2012 77 465\u2013470. (https:\/\/doi.org\/10.1111\/j1365-2265.2012.04397.x)"},{"key":"bib9","series-title":"Lancet","first-page":"126","article-title":"Human monoclonal thyroid stimulating autoantibody","volume":"362","author":"Sanders J","year":"2003","unstructured":"Sanders J\n, \nEvans M\n, \nPremawardhana LD\n, et al.\n Human monoclonal thyroid stimulating autoantibody. Lancet 2003 362 126\u2013128. (https:\/\/doi.org\/10.1016\/s0140-6736(03)13866-4)"},{"key":"bib10","series-title":"Thyroid","first-page":"735","article-title":"A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity","volume":"18","author":"Sanders J","year":"2008","unstructured":"Sanders J\n, \nEvans M\n, \nBetterle C\n, et al.\n A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity. Thyroid 2008 18 735\u2013746. (https:\/\/doi.org\/10.1089\/thy.2007.0327)"},{"key":"bib11","series-title":"Thyroid","first-page":"395","article-title":"Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody","volume":"17","author":"Sanders J","year":"2007","unstructured":"Sanders J\n, \nChirgadze DY\n, \nSanders P\n, et al.\n Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 2007 17 395\u2013410. (https:\/\/doi.org\/10.1089\/thy.2007.0034)"},{"key":"bib12","series-title":"J Mol Endocrinol","first-page":"81","article-title":"Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody","volume":"46","author":"Sanders P","year":"2011","unstructured":"Sanders P\n, \nYoung S\n, \nSanders J\n, et al.\n Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody. J Mol Endocrinol 2011 46 81\u201399. (https:\/\/doi.org\/10.1530\/JME-10-0127)"},{"key":"bib13","series-title":"Nature","first-page":"688","article-title":"Structures of full-length glycoprotein hormone receptor signalling complexes","volume":"598","author":"Duan J","year":"2021","unstructured":"Duan J\n, \nXu P\n, \nCheng X\n, et al.\n Structures of full-length glycoprotein hormone receptor signalling complexes. Nature 2021 598 688\u2013692. (https:\/\/doi.org\/10.1038\/s41586-021-03924-2)"},{"key":"bib14","series-title":"Nat Commun","first-page":"519","article-title":"Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor","volume":"14","author":"Duan J","year":"2023","unstructured":"Duan J\n, \nXu P\n, \nZhang H\n, et al.\n Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. Nat Commun 2023 14 519. (https:\/\/doi.org\/10.1038\/s41467-023-36170-3)"},{"key":"bib15","series-title":"Nature","first-page":"846","article-title":"Autoantibody mimicry of hormone action at the thyrotropin receptor","volume":"609","author":"Faust B","year":"2022","unstructured":"Faust B\n, \nBillesb\u00f8lle CB\n, \nSuomivuori CM\n, et al.\n Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 2022 609 846\u2013853. (https:\/\/doi.org\/10.1038\/s41586-022-05159-1)"},{"key":"bib16","series-title":"J Mol Endocrinol","first-page":"117","article-title":"Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain","volume":"62","author":"Miller-Gallacher J","year":"2019","unstructured":"Miller-Gallacher J\n, \nSanders P\n, \nYoung S\n, et al.\n Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain. J Mol Endocrinol 2019 62 117\u2013128. (https:\/\/doi.org\/10.1530\/jME-18-0213)"},{"key":"bib17","series-title":"J Clin Endocrinol Metab","first-page":"E871","article-title":"Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in graves\u2019 disease","volume":"100","author":"Rapoport B","year":"2015","unstructured":"Rapoport B\n, \nAliesky HA\n, \nChen CR\n, et al.\n Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in graves\u2019 disease. J Clin Endocrinol Metab 2015 100 E871\u2013E875. (https:\/\/doi.org\/10.1210\/jc.2015-1528)"},{"key":"bib18","series-title":"Nat Rev Dis Primers","first-page":"52","article-title":"Graves\u2019 disease","volume":"6","author":"Davies TF","year":"2020","unstructured":"Davies TF\n, \nAndersen S\n, \nLatif R\n, et al.\n Graves\u2019 disease. Nat Rev Dis Primers 2020 6 52. (https:\/\/doi.org\/10.1038\/s41572-020-0184-y)"},{"key":"bib19","series-title":"J Biol Chem","first-page":"518","article-title":"Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor","volume":"282","author":"Kleinau G","year":"2007","unstructured":"Kleinau G\n, \nClaus M\n, \nJaeschke H\n, et al.\n Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor. J Biol Chem 2007 282 518\u2013525. (https:\/\/doi.org\/10.1074\/jbc.M606176200)"},{"key":"bib20","series-title":"Nature","first-page":"259","article-title":"Structure of the full-length glucagon class B G-protein-coupled receptor","volume":"546","author":"Zhang H","year":"2017","unstructured":"Zhang H\n, \nQiao A\n, \nYang D\n, et al.\n Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 2017 546 259\u2013264. (https:\/\/doi.org\/10.1038\/nature22363)"},{"key":"bib21","series-title":"Nature","first-page":"106","article-title":"Structure of the glucagon receptor in complex with a glucagon analogue","volume":"553","author":"Zhang H","year":"2018","unstructured":"Zhang H\n, \nQiao A\n, \nYang L\n, et al.\n Structure of the glucagon receptor in complex with a glucagon analogue. Nature 2018 553 106\u2013110. (https:\/\/doi.org\/10.1038\/nature25153)"},{"key":"bib22","series-title":"Trends Pharmacol Sci","first-page":"17","article-title":"Diversity and modularity of G protein-coupled receptor structures","volume":"33","author":"Katritch V","year":"2012","unstructured":"Katritch V\n, \nCherezov V\n & \nStevens RC\n\n. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci 2012 33 17\u201327. (https:\/\/doi.org\/10.1016\/j.tips.2011.09.003)"},{"key":"bib23","series-title":"Methods Neurosci","first-page":"366","article-title":"Integrated methods for the construction of three dimensional models and computational probing of structure function relations in G protein-coupled receptors","volume":"25","author":"Ballesteros JA","year":"1995","unstructured":"Ballesteros JA\n & \nWeinstein H\n\n. Integrated methods for the construction of three dimensional models and computational probing of structure function relations in G protein-coupled receptors. Methods Neurosci 1995 25 366\u2013428. (https:\/\/doi.org\/10.1016\/S1043-9471(05)80049-7)"},{"key":"bib24","series-title":"Mol Endocrinol","first-page":"725","article-title":"Somatic mutations causing constitutive activity of the TSH receptor are the major cause of hyperfunctional thyroid adenomas: identification of additional mutations activating both the cAMP and inositolphosphate-Ca11 cascades","volume":"9","author":"Parma J","year":"1995","unstructured":"Parma J\n, \nVan Sande J\n, \nSwillens S\n, et al.\n Somatic mutations causing constitutive activity of the TSH receptor are the major cause of hyperfunctional thyroid adenomas: identification of additional mutations activating both the cAMP and inositolphosphate-Ca11 cascades. Mol Endocrinol 1995 9 725\u2013733. (https:\/\/doi.org\/10.1210\/mend.9.6.8592518)"},{"key":"bib25","series-title":"FEBS Lett","first-page":"469","article-title":"Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain","volume":"409","author":"Duprez L","year":"1997","unstructured":"Duprez L\n, \nParma J\n, \nCostagliola S\n, et al.\n Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 1997 409 469\u2013474. (https:\/\/doi.org\/10.1016\/s0014-5793(97)00532-2)"},{"key":"bib26","series-title":"J Mol Endocrinol","first-page":"137","article-title":"Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor","volume":"49","author":"N\u00fa\u00f1ez Miguel R","year":"2012","unstructured":"N\u00fa\u00f1ez Miguel R\n, \nSanders J\n, \nSanders P\n, et al.\n Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor. J Mol Endocrinol 2012 49 137\u2013151. (https:\/\/doi.org\/10.1530\/JME-12-0040)"},{"key":"bib27","series-title":"Thyroid","first-page":"1195","article-title":"Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH","volume":"16","author":"Sanders J","year":"2006","unstructured":"Sanders J\n, \nBolton J\n, \nSanders P\n, et al.\n Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH. Thyroid 2006 16 1195\u20131206. (https:\/\/doi.org\/10.1089\/thy.2006.16.1195)"},{"key":"bib28","series-title":"Clin Endocrinol","first-page":"878","article-title":"TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy \u2013 results from a phase I clinical trial","volume":"96","author":"Furmaniak J","year":"2022","unstructured":"Furmaniak J\n, \nSanders J\n, \nSanders P\n, et al.\n TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy \u2013 results from a phase I clinical trial. Clin Endocrinol 2022 96 878\u2013887. (https:\/\/doi.org\/10.1111\/cen.14681)"},{"key":"bib29","series-title":"Endocr J","first-page":"897","article-title":"Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial","volume":"72","author":"Noh JY","year":"2025","unstructured":"Noh JY\n, \nWatanabe N\n, \nIto K\n, et al.\n Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial. Endocr J 2025 72 897\u2013909. (https:\/\/doi.org\/10.1507\/endocrj.EJ25-0043)"},{"key":"bib30","series-title":"Eur Thyroid J","article-title":"The evolving therapeutic landscape of Graves\u2019 disease in adults: present and future","volume":"14","author":"Stan MN","year":"2025","unstructured":"Stan MN\n & \nDosiou C\n\n. The evolving therapeutic landscape of Graves\u2019 disease in adults: present and future. Eur Thyroid J 2025 14 e250078. (https:\/\/doi.org\/10.1530\/ETJ-25-0078)"},{"key":"bib31","series-title":"Endocrine J","first-page":"1285","article-title":"Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases","volume":"69","author":"Nagayama Y","year":"2022","unstructured":"Nagayama Y\n & \nNishihara E\n\n. Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases. Endocrine J 2022 69 1285\u20131293. (https:\/\/doi.org\/10.1507\/endocrj.EJ22-0391)"},{"key":"bib32","series-title":"Thyroid","first-page":"1597","article-title":"Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, Graves\u2019 disease, and Graves\u2019 ophthalmopathy","volume":"31","author":"Ryder M","year":"2021","unstructured":"Ryder M\n, \nWentworth M\n, \nAlgeciras-Schimnich A\n, et al.\n Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, Graves\u2019 disease, and Graves\u2019 ophthalmopathy. Thyroid 2021 31 1597\u20131602. (https:\/\/doi.org\/10.1089\/thy.2021.0053)"},{"key":"bib33","series-title":"Endocrinology","first-page":"3427","article-title":"Identification of key amino acid residues in a thyrotropin receptor monoclonal antibody epitope provides insight into its inverse agonist and antagonist properties","volume":"149","author":"Chen CR","year":"2008","unstructured":"Chen CR\n, \nMcLachlan SM\n & \nRapoport B\n\n. Identification of key amino acid residues in a thyrotropin receptor monoclonal antibody epitope provides insight into its inverse agonist and antagonist properties. Endocrinology 2008 149 3427\u20133434. (https:\/\/doi.org\/10.1210\/en.2008-0207)"},{"key":"bib34","series-title":"Endocrinology","first-page":"3401","article-title":"A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor Hinge region as well as to the leucine-rich domain","volume":"150","author":"Chen CR","year":"2009","unstructured":"Chen CR\n, \nMcLachlan SM\n & \nRapoport B\n\n. A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor Hinge region as well as to the leucine-rich domain. Endocrinology 2009 150 3401\u20133408. (https:\/\/doi.org\/10.1210\/en.2008-1800)"},{"key":"bib1","series-title":"J Mol Endocrinol","article-title":"Structure of full-length TSH receptor in complex with antibody K1-70\u2122","volume":"70","author":"N\u00fa\u00f1ez MR","year":"2022","unstructured":"N\u00fa\u00f1ez MR\n, \nSanders P\n, \nAllen L\n, et al.\n Structure of full-length TSH receptor in complex with antibody K1-70\u2122. J Mol Endocrinol 2022 70 e220120. (https:\/\/doi.org\/10.1530\/JME-22-0120)"},{"key":"bib2","series-title":"Endocr Rev","first-page":"106","article-title":"Autoantibodies to the thyrotropin receptor","volume":"9","author":"Rees Smith B","year":"1988","unstructured":"Rees Smith B\n, \nMcLachlan SM\n & \nFurmaniak J\n\n. Autoantibodies to the thyrotropin receptor. Endocr Rev 1988 9 106\u2013121. (https:\/\/doi.org\/10.1210\/edrv-9-1-106)"},{"key":"bib3","series-title":"J Clin Endocrinol Metab","first-page":"734","article-title":"Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves\u2019 disease and Hashimoto\u2019s thyroiditis","volume":"46","author":"Endo K","year":"1978","unstructured":"Endo K\n, \nKasagi K\n, \nKonishi J\n, et al.\n Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves\u2019 disease and Hashimoto\u2019s thyroiditis. J Clin Endocrinol Metab 1978 46 734\u2013739. (https:\/\/doi.org\/10.1210\/jcem-46-5-734)"},{"key":"bib4","series-title":"Clin Endocrinol","first-page":"207","article-title":"Thyroid-stimulating immunoglobulins in ophthalmic Graves\u2019 disease","volume":"6","author":"Teng CS","year":"1977","unstructured":"Teng CS\n, \nSmith BR\n, \nClayton B\n, et al.\n Thyroid-stimulating immunoglobulins in ophthalmic Graves\u2019 disease. Clin Endocrinol 1977 6 207\u2013211. (https:\/\/doi.org\/10.1111\/j.1365-2265.1977.tb03316.x)"},{"key":"bib5","series-title":"Clin Endocrinol","first-page":"404","article-title":"Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample","volume":"73","author":"Evans M","year":"2010","unstructured":"Evans M\n, \nSanders J\n, \nTagami T\n, et al.\n Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrinol 2010 73 404\u2013412. (https:\/\/doi.org\/10.1111\/j.1365-2265.2010.03831.x)"},{"key":"bib6","series-title":"J Thyroid Res","article-title":"Changes of TSH-stimulation blocking antibody (TSBAb) and thyroid stimulating antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive patients with hyperthyroidism: re-evaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients","volume":"2012","author":"Takasu N","year":"2012","unstructured":"Takasu N\n, \nKonishi J\n, \nLida Y\n, et al.\n Changes of TSH-stimulation blocking antibody (TSBAb) and thyroid stimulating antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive patients with hyperthyroidism: re-evaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients. J Thyroid Res 2012 2012 182176. (https:\/\/doi.org\/10.1155\/2012\/182176)"},{"key":"bib7","series-title":"Clin Endocrinol","first-page":"369","article-title":"Thyrotropin receptor antibody concentration and activity, several years after treatment for Graves\u2019 disease","volume":"90","author":"Nalla P","year":"2019","unstructured":"Nalla P\n, \nYoung S\n, \nSanders J\n, et al.\n Thyrotropin receptor antibody concentration and activity, several years after treatment for Graves\u2019 disease. Clin Endocrinol 2019 90 369\u2013374. (https:\/\/doi.org\/10.1111\/cen.13908)"},{"key":"bib8","series-title":"Clin Endocrinol","first-page":"465","article-title":"Thyrotropin receptor antibody characteristics in a woman with long-standing Hashimoto\u2019s who developed Graves\u2019 disease and pretibial myxoedema","volume":"77","author":"Kamath C","year":"2012","unstructured":"Kamath C\n, \nYoung S\n, \nKabelis K\n, et al.\n Thyrotropin receptor antibody characteristics in a woman with long-standing Hashimoto\u2019s who developed Graves\u2019 disease and pretibial myxoedema. Clin Endocrinol 2012 77 465\u2013470. (https:\/\/doi.org\/10.1111\/j1365-2265.2012.04397.x)"},{"key":"bib9","series-title":"Lancet","first-page":"126","article-title":"Human monoclonal thyroid stimulating autoantibody","volume":"362","author":"Sanders J","year":"2003","unstructured":"Sanders J\n, \nEvans M\n, \nPremawardhana LD\n, et al.\n Human monoclonal thyroid stimulating autoantibody. Lancet 2003 362 126\u2013128. (https:\/\/doi.org\/10.1016\/s0140-6736(03)13866-4)"},{"key":"bib10","series-title":"Thyroid","first-page":"735","article-title":"A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity","volume":"18","author":"Sanders J","year":"2008","unstructured":"Sanders J\n, \nEvans M\n, \nBetterle C\n, et al.\n A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity. Thyroid 2008 18 735\u2013746. (https:\/\/doi.org\/10.1089\/thy.2007.0327)"},{"key":"bib11","series-title":"Thyroid","first-page":"395","article-title":"Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody","volume":"17","author":"Sanders J","year":"2007","unstructured":"Sanders J\n, \nChirgadze DY\n, \nSanders P\n, et al.\n Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 2007 17 395\u2013410. (https:\/\/doi.org\/10.1089\/thy.2007.0034)"},{"key":"bib12","series-title":"J Mol Endocrinol","first-page":"81","article-title":"Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody","volume":"46","author":"Sanders P","year":"2011","unstructured":"Sanders P\n, \nYoung S\n, \nSanders J\n, et al.\n Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody. J Mol Endocrinol 2011 46 81\u201399. (https:\/\/doi.org\/10.1530\/JME-10-0127)"},{"key":"bib13","series-title":"Nature","first-page":"688","article-title":"Structures of full-length glycoprotein hormone receptor signalling complexes","volume":"598","author":"Duan J","year":"2021","unstructured":"Duan J\n, \nXu P\n, \nCheng X\n, et al.\n Structures of full-length glycoprotein hormone receptor signalling complexes. Nature 2021 598 688\u2013692. (https:\/\/doi.org\/10.1038\/s41586-021-03924-2)"},{"key":"bib14","series-title":"Nat Commun","first-page":"519","article-title":"Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor","volume":"14","author":"Duan J","year":"2023","unstructured":"Duan J\n, \nXu P\n, \nZhang H\n, et al.\n Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. Nat Commun 2023 14 519. (https:\/\/doi.org\/10.1038\/s41467-023-36170-3)"},{"key":"bib15","series-title":"Nature","first-page":"846","article-title":"Autoantibody mimicry of hormone action at the thyrotropin receptor","volume":"609","author":"Faust B","year":"2022","unstructured":"Faust B\n, \nBillesb\u00f8lle CB\n, \nSuomivuori CM\n, et al.\n Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature 2022 609 846\u2013853. (https:\/\/doi.org\/10.1038\/s41586-022-05159-1)"},{"key":"bib16","series-title":"J Mol Endocrinol","first-page":"117","article-title":"Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain","volume":"62","author":"Miller-Gallacher J","year":"2019","unstructured":"Miller-Gallacher J\n, \nSanders P\n, \nYoung S\n, et al.\n Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain. J Mol Endocrinol 2019 62 117\u2013128. (https:\/\/doi.org\/10.1530\/jME-18-0213)"},{"key":"bib17","series-title":"J Clin Endocrinol Metab","first-page":"E871","article-title":"Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in graves\u2019 disease","volume":"100","author":"Rapoport B","year":"2015","unstructured":"Rapoport B\n, \nAliesky HA\n, \nChen CR\n, et al.\n Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in graves\u2019 disease. J Clin Endocrinol Metab 2015 100 E871\u2013E875. (https:\/\/doi.org\/10.1210\/jc.2015-1528)"},{"key":"bib18","series-title":"Nat Rev Dis Primers","first-page":"52","article-title":"Graves\u2019 disease","volume":"6","author":"Davies TF","year":"2020","unstructured":"Davies TF\n, \nAndersen S\n, \nLatif R\n, et al.\n Graves\u2019 disease. Nat Rev Dis Primers 2020 6 52. (https:\/\/doi.org\/10.1038\/s41572-020-0184-y)"},{"key":"bib19","series-title":"J Biol Chem","first-page":"518","article-title":"Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor","volume":"282","author":"Kleinau G","year":"2007","unstructured":"Kleinau G\n, \nClaus M\n, \nJaeschke H\n, et al.\n Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor. J Biol Chem 2007 282 518\u2013525. (https:\/\/doi.org\/10.1074\/jbc.M606176200)"},{"key":"bib20","series-title":"Nature","first-page":"259","article-title":"Structure of the full-length glucagon class B G-protein-coupled receptor","volume":"546","author":"Zhang H","year":"2017","unstructured":"Zhang H\n, \nQiao A\n, \nYang D\n, et al.\n Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 2017 546 259\u2013264. (https:\/\/doi.org\/10.1038\/nature22363)"},{"key":"bib21","series-title":"Nature","first-page":"106","article-title":"Structure of the glucagon receptor in complex with a glucagon analogue","volume":"553","author":"Zhang H","year":"2018","unstructured":"Zhang H\n, \nQiao A\n, \nYang L\n, et al.\n Structure of the glucagon receptor in complex with a glucagon analogue. Nature 2018 553 106\u2013110. (https:\/\/doi.org\/10.1038\/nature25153)"},{"key":"bib22","series-title":"Trends Pharmacol Sci","first-page":"17","article-title":"Diversity and modularity of G protein-coupled receptor structures","volume":"33","author":"Katritch V","year":"2012","unstructured":"Katritch V\n, \nCherezov V\n & \nStevens RC\n\n. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci 2012 33 17\u201327. (https:\/\/doi.org\/10.1016\/j.tips.2011.09.003)"},{"key":"bib23","series-title":"Methods Neurosci","first-page":"366","article-title":"Integrated methods for the construction of three dimensional models and computational probing of structure function relations in G protein-coupled receptors","volume":"25","author":"Ballesteros JA","year":"1995","unstructured":"Ballesteros JA\n & \nWeinstein H\n\n. Integrated methods for the construction of three dimensional models and computational probing of structure function relations in G protein-coupled receptors. Methods Neurosci 1995 25 366\u2013428. (https:\/\/doi.org\/10.1016\/S1043-9471(05)80049-7)"},{"key":"bib24","series-title":"Mol Endocrinol","first-page":"725","article-title":"Somatic mutations causing constitutive activity of the TSH receptor are the major cause of hyperfunctional thyroid adenomas: identification of additional mutations activating both the cAMP and inositolphosphate-Ca11 cascades","volume":"9","author":"Parma J","year":"1995","unstructured":"Parma J\n, \nVan Sande J\n, \nSwillens S\n, et al.\n Somatic mutations causing constitutive activity of the TSH receptor are the major cause of hyperfunctional thyroid adenomas: identification of additional mutations activating both the cAMP and inositolphosphate-Ca11 cascades. Mol Endocrinol 1995 9 725\u2013733. (https:\/\/doi.org\/10.1210\/mend.9.6.8592518)"},{"key":"bib25","series-title":"FEBS Lett","first-page":"469","article-title":"Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain","volume":"409","author":"Duprez L","year":"1997","unstructured":"Duprez L\n, \nParma J\n, \nCostagliola S\n, et al.\n Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 1997 409 469\u2013474. (https:\/\/doi.org\/10.1016\/s0014-5793(97)00532-2)"},{"key":"bib26","series-title":"J Mol Endocrinol","first-page":"137","article-title":"Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor","volume":"49","author":"N\u00fa\u00f1ez Miguel R","year":"2012","unstructured":"N\u00fa\u00f1ez Miguel R\n, \nSanders J\n, \nSanders P\n, et al.\n Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor. J Mol Endocrinol 2012 49 137\u2013151. (https:\/\/doi.org\/10.1530\/JME-12-0040)"},{"key":"bib27","series-title":"Thyroid","first-page":"1195","article-title":"Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH","volume":"16","author":"Sanders J","year":"2006","unstructured":"Sanders J\n, \nBolton J\n, \nSanders P\n, et al.\n Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH. Thyroid 2006 16 1195\u20131206. (https:\/\/doi.org\/10.1089\/thy.2006.16.1195)"},{"key":"bib28","series-title":"Clin Endocrinol","first-page":"878","article-title":"TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy \u2013 results from a phase I clinical trial","volume":"96","author":"Furmaniak J","year":"2022","unstructured":"Furmaniak J\n, \nSanders J\n, \nSanders P\n, et al.\n TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy \u2013 results from a phase I clinical trial. Clin Endocrinol 2022 96 878\u2013887. (https:\/\/doi.org\/10.1111\/cen.14681)"},{"key":"bib29","series-title":"Endocr J","first-page":"897","article-title":"Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial","volume":"72","author":"Noh JY","year":"2025","unstructured":"Noh JY\n, \nWatanabe N\n, \nIto K\n, et al.\n Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial. Endocr J 2025 72 897\u2013909. (https:\/\/doi.org\/10.1507\/endocrj.EJ25-0043)"},{"key":"bib30","series-title":"Eur Thyroid J","article-title":"The evolving therapeutic landscape of Graves\u2019 disease in adults: present and future","volume":"14","author":"Stan MN","year":"2025","unstructured":"Stan MN\n & \nDosiou C\n\n. The evolving therapeutic landscape of Graves\u2019 disease in adults: present and future. Eur Thyroid J 2025 14 e250078. (https:\/\/doi.org\/10.1530\/ETJ-25-0078)"},{"key":"bib31","series-title":"Endocrine J","first-page":"1285","article-title":"Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases","volume":"69","author":"Nagayama Y","year":"2022","unstructured":"Nagayama Y\n & \nNishihara E\n\n. Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases. Endocrine J 2022 69 1285\u20131293. (https:\/\/doi.org\/10.1507\/endocrj.EJ22-0391)"},{"key":"bib32","series-title":"Thyroid","first-page":"1597","article-title":"Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, Graves\u2019 disease, and Graves\u2019 ophthalmopathy","volume":"31","author":"Ryder M","year":"2021","unstructured":"Ryder M\n, \nWentworth M\n, \nAlgeciras-Schimnich A\n, et al.\n Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, Graves\u2019 disease, and Graves\u2019 ophthalmopathy. Thyroid 2021 31 1597\u20131602. (https:\/\/doi.org\/10.1089\/thy.2021.0053)"},{"key":"bib33","series-title":"Endocrinology","first-page":"3427","article-title":"Identification of key amino acid residues in a thyrotropin receptor monoclonal antibody epitope provides insight into its inverse agonist and antagonist properties","volume":"149","author":"Chen CR","year":"2008","unstructured":"Chen CR\n, \nMcLachlan SM\n & \nRapoport B\n\n. Identification of key amino acid residues in a thyrotropin receptor monoclonal antibody epitope provides insight into its inverse agonist and antagonist properties. Endocrinology 2008 149 3427\u20133434. (https:\/\/doi.org\/10.1210\/en.2008-0207)"},{"key":"bib34","series-title":"Endocrinology","first-page":"3401","article-title":"A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor Hinge region as well as to the leucine-rich domain","volume":"150","author":"Chen CR","year":"2009","unstructured":"Chen CR\n, \nMcLachlan SM\n & \nRapoport B\n\n. A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor Hinge region as well as to the leucine-rich domain. Endocrinology 2009 150 3401\u20133408. 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