The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Nature. 2021 Oct;598(7882):688-692. doi: 10.1038/s41586-021-03924-2. Epub 2021 Sep 22.
Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs. They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain. 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), and one of the structures also contains Org43553, an allosteric agonist. 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糖蛋白激素，与卵泡刺激素和促甲状腺激素有关。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。它们通过与大的细胞外结构域结合，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 的四个冷冻电镜结构：野生型受体在非激活和激活状态下的两个结构；以及两个组成型激活突变受体的结构。活性结构与绒毛膜促性腺激素和刺激性 G 蛋白（G）结合，其中一个结构还包含别构激动剂 Org43553。这些结构揭示了受体激活的独特“推-拉”机制，其中细胞外结构域被结合的激素推动，同时被跨膜域附近延伸的铰链环拉动。来自细胞外域和跨膜域之间界面的铰链 C 末端环上的高度保守的 10 个残基片段（P10）作为连接的激动剂，诱导跨膜域和 G 蛋白偶联的构象变化。Org43553 结合到跨膜域的一个口袋中，并与 P10 直接相互作用，进一步稳定了活性构象。这些结构共同为理解糖蛋白激素受体的信号转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。
