7FIJ

luteinizing hormone/choriogonadotropin receptor

Summary for 7FIJ

• Entry DOI: 10.2210/pdb7fij/pdb
• EMDB information: 31599
• Descriptor: Lutropin-choriogonadotropic hormone receptor (1 entity in total)
• Functional Keywords: glycoprotein hormone receptor, gpcr, luteinizing hormone, choriogonadotropin receptor, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 78629.80

Authors

Duan, J.,Xu, P.,Cheng, X.,Mao, C.,Croll, T.,He, X.,Shi, J.,Luan, X.,Yin, W.,You, E.,Liu, Q.,Zhang, S.,Jiang, H.,Zhang, Y.,Jiang, Y.,Xu, H.E. (deposition date: 2021-07-31, release date: 2021-09-29, Last modification date: 2024-10-23)

Primary citation

Duan, J.,Xu, P.,Cheng, X.,Mao, C.,Croll, T.,He, X.,Shi, J.,Luan, X.,Yin, W.,You, E.,Liu, Q.,Zhang, S.,Jiang, H.,Zhang, Y.,Jiang, Y.,Xu, H.E.
Structures of full-length glycoprotein hormone receptor signalling complexes.
Nature, 598:688-692, 2021

PubMed Abstract: 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.

PubMed: 34552239
DOI: 10.1038/s41586-021-03924-2

Experimental method

ELECTRON MICROSCOPY (3.8 Å)