8I2G

FSHR-Follicle stimulating hormone-compound 716340-Gs complex

Summary for 8I2G

• Entry DOI: 10.2210/pdb8i2g/pdb
• EMDB information: 35135
• Descriptor: chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas, PALMITIC ACID, MYRISTIC ACID, ... (13 entities in total)
• Functional Keywords: follicle stimulating hormone, fsh, gpcr, gs-protein, hormone
• Biological source: Cricetulus griseus (Chinese hamster); More
• Total number of polymer chains: 7
• Total formula weight: 196969.02

Authors

Duan, J.,Xu, P.,Yang, J.,Ji, Y.,Zhang, H.,Mao, C.,Luan, X.,Jiang, Y.,Zhang, Y.,Zhang, S.,Xu, H.E. (deposition date: 2023-01-14, release date: 2023-03-29, Last modification date: 2023-04-05)

Primary citation

Duan, J.,Xu, P.,Zhang, H.,Luan, X.,Yang, J.,He, X.,Mao, C.,Shen, D.D.,Ji, Y.,Cheng, X.,Jiang, H.,Jiang, Y.,Zhang, S.,Zhang, Y.,Xu, H.E.
Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor.
Nat Commun, 14:519-519, 2023

PubMed Abstract: Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.

PubMed: 36720854
DOI: 10.1038/s41467-023-36170-3

Experimental method

ELECTRON MICROSCOPY (2.8 Å)