Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor

Jia Duan, Peiyu Xu, Huibing Zhang, Xiaodong Luan, Jiaqi Yang, Xinheng He, Chunyou Mao, Dan-Dan Shen, Yujie Ji, Xi Cheng, Hualiang Jiang, Yi Jiang, Shuyang Zhang (), Yan Zhang () and H. Eric Xu ()
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Jia Duan: Chinese Academy of Sciences
Peiyu Xu: Chinese Academy of Sciences
Huibing Zhang: Zhejiang University School of Medicine
Xiaodong Luan: Peking Union Medical College and Chinese Academy of Medical Sciences
Jiaqi Yang: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Chunyou Mao: Zhejiang University School of Medicine
Dan-Dan Shen: Zhejiang University School of Medicine
Yujie Ji: Chinese Academy of Sciences
Xi Cheng: Chinese Academy of Sciences
Hualiang Jiang: Chinese Academy of Sciences
Yi Jiang: Lingang Laboratory
Shuyang Zhang: Peking Union Medical College and Chinese Academy of Medical Sciences
Yan Zhang: Zhejiang University School of Medicine
H. Eric Xu: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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 H6157.42 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.

Date: 2023
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DOI: 10.1038/s41467-023-36170-3

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