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

Author:

Duan Jia,Xu PeiyuORCID,Zhang HuibingORCID,Luan XiaodongORCID,Yang Jiaqi,He XinhengORCID,Mao ChunyouORCID,Shen Dan-Dan,Ji Yujie,Cheng XiORCID,Jiang HualiangORCID,Jiang YiORCID,Zhang ShuyangORCID,Zhang YanORCID,Xu H. EricORCID

Abstract

AbstractFollicle 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.

Funder

Chinese Ministry of Science and Technology | Department of S and T for Social Development

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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