Thyroid stimulating hormone (TSH), through activation of its G protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone (TH), an essential metabolic hormone^1-3. Aberrant signaling of TSHR by autoantibodies causes Graves’ disease and hypothyroidism that affect millions of patients worldwide⁴. Here we report the active structures of TSHR with TSH and an activating autoantibody M22⁵, both bound to an allosteric agonist ML-109⁶, as well as an inactivated TSHR structure with inhibitory antibody K1-70⁷. Both TSH and M22 push the extracellular domain (ECD) of TSHR into the upright active conformation. In contrast, K1-70 blocks TSH binding and is incapable of pushing the ECD to 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 10-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain⁸. One surprisingly feature is that there are over 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, thus providing the molecular basis for Graves’ disease.

促甲状腺激素 (TSH) 通过激活其 G 蛋白偶联促甲状腺激素受体 (TSHR)，控制甲状腺激素 (TH) 的合成，这是一种必需的代谢激素^1-3。自身抗体引起的 TSHR 异常信号传导会导致 Graves 病和甲状腺功能减退，影响全球数百万患者⁴。在这里，我们报告了具有 TSH 和激活性自身抗体 M22 ⁵的 TSHR 的活性结构，两者都与变构激动剂 ML-109 ⁶结合，以及具有抑制性抗体 K1-70 ^{7的灭活 TSHR 结构}. TSH 和 M22 都将 TSHR 的细胞外结构域 (ECD) 推入直立的活性构象。相比之下，K1-70 阻断 TSH 结合，无法将 ECD 推向直立构象。TSHR 与促黄体激素-绒毛膜促性腺激素受体 (LHCGR) 的活性和灭活结构的比较揭示了糖蛋白激素受体的普遍激活机制，其中来自铰链 C 末端环的保守 10 残基片段 (P10) 介导ECD 与 TSHR 跨膜结构域⁸的相互作用。一个令人惊讶的特征是 TSHR 周围有超过 15 种胆固醇，支持其在脂筏中的优先位置⁹. 这些结构还突出了 TSH 和自身抗体 M22 激活 TSHR 的类似 ECD 推动机制，从而为 Graves 病提供了分子基础。