Structures of full-length glycoprotein hormone receptor signalling complexes

Jia Duan, Peiyu Xu, Xi Cheng, Chunyou Mao, Tristan Croll, Xinheng He, Jingjing Shi, Xiaodong Luan, Wanchao Yin, Erli You, Qiufeng Liu, Shuyang Zhang, Hualiang Jiang, Yan Zhang (), Yi Jiang () and H. Eric Xu ()
Additional contact information
Jia Duan: Chinese Academy of Sciences
Peiyu Xu: Chinese Academy of Sciences
Xi Cheng: Chinese Academy of Sciences
Chunyou Mao: Zhejiang University School of Medicine
Tristan Croll: University of Cambridge
Xinheng He: Chinese Academy of Sciences
Jingjing Shi: Chinese Academy of Sciences
Xiaodong Luan: Tsinghua University
Wanchao Yin: Chinese Academy of Sciences
Erli You: Chinese Academy of Sciences
Qiufeng Liu: Chinese Academy of Sciences
Shuyang Zhang: Tsinghua University
Hualiang Jiang: Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine
Yi Jiang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences

Nature, 2021, vol. 598, issue 7882, 688-692

Abstract: Abstract Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone1,2. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs3–6. 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 (Gs), 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.

Date: 2021
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DOI: 10.1038/s41586-021-03924-2

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