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Hormone- and antibody-mediated activation of the thyrotropin receptor.

Published:8 August 2022 DOI: 10.1038/s41586-022-05173-3 PMID: 35940204
Jia Duan, Peiyu Xu, Xiaodong Luan, Yujie Ji, Xinheng He, Ning Song, Qingning Yuan, Ye Jin, Xi Cheng, Hualiang Jiang, Jie Zheng, Shuyang Zhang, Yi Jiang, H. Eric Xu

Abstract

Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone—an essential metabolic hormone1–3. Aberrant signalling of TSHR by autoantibodies causes Graves’ disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide4. Here we report the active structures of TSHR with TSH and the activating autoantibody M225, both bound to the allosteric agonist ML-1096, as well as an inactivated TSHR structure with the inhibitory antibody K1-707. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain8. One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts9. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves’ disease. Thyroid-stimulating hormone and autoantibody M22 push the extracellular domain of the thyrotropin receptor into an upright active conformation, revealing a universal activation mechanism of glycoprotein hormone receptors and providing the molecular basis of Graves’ disease, hypothyroidism and Hashimoto’s disease.

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Procduct Name CAS Molecular Formula Supplier Price
ML-109 1186649-91-1 C31H29N3O5 43 suppliers Inquiry
ML-109 1186649-91-1 C31H29N3O5 43 suppliers Inquiry
ML-109 1186649-91-1 C31H29N3O5 43 suppliers Inquiry
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