Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone^1,2. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs^3,4,5,6. They activate the same G-protein-coupled receptor, luteinizing hormone–choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain³. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G_s), and one of the structures also contains Org43553, an allosteric agonist⁷. The structures reveal a distinct ‘push-and-pull’ mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.

黄体生成素和绒毛膜促性腺激素是与促卵泡激素和促甲状腺激素^1,2相关的糖蛋白激素。黄体生成素和绒毛膜促性腺激素对人类生殖至关重要，是重要的治疗药物^3,4,5,6。^{它们通过结合到大的细胞外结构域3}来激活相同的 G 蛋白偶联受体，黄体生成素 - 绒毛膜促性腺激素受体 (LHCGR) 。在这里，我们报告了 LHCGR 的四个冷冻电子显微镜结构：处于非活性和活性状态的野生型受体的两个结构；和组成型活性突变受体的两个结构。活性结构与绒毛膜促性腺激素和刺激性 G 蛋白 (G _s)，其中一个结构还包含 Org43553，一种变构激动剂⁷. 这些结构揭示了受体激活的独特“推拉”机制，其中细胞外域被结合的激素推动，并被跨膜域旁边的延伸铰链环拉动。来自细胞外结构域和跨膜结构域之间界面处铰链 C 末端环的高度保守的 10 残基片段 (P10) 作为栓系激动剂起作用，以诱导跨膜结构域和 G 蛋白偶联的构象变化。Org43553 与跨膜结构域的口袋结合并直接与 P10 相互作用，从而进一步稳定活性构象。总之，这些结构为理解糖蛋白激素受体的信号传导提供了一个通用模型，并为内分泌疾病的药物发现奠定了基础。