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

文献类型：期刊论文

作者Duan, Jia1,2; Xu, Peiyu1; Zhang, Huibing3,5,6,7; Luan, Xiaodong8,9,10,11; Yang, Jiaqi1; He, Xinheng1,2; Mao, Chunyou3,5,6,7; Shen, Dan-Dan3,5,6,7; Ji, Yujie1,2; Cheng, Xi1
刊名NATURE COMMUNICATIONS
出版日期2023-01-31
卷号14期号:1页码:12
DOI10.1038/s41467-023-36170-3
通讯作者Zhang, Shuyang(shuyangzhang103@nrdrs.org) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要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 21f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615(7.42) 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. Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.
WOS关键词GLYCOPROTEIN HORMONES ; STRUCTURAL BIOLOGY ; ECTODOMAIN ; THYROTROPIN ; COMPLEX ; GENE
资助项目Ministry of Science and Technology (China)[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81922071] ; CAMS Innovation Fund for Medical Sciences[2021-CAMS-JZ004] ; CAMS Innovation Fund for Medical Sciences[2021-I2M-1-003] ; Tsinghua University-Peking University Center for Life Sciences[045-61020100121] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipal[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05] ; Zhejiang Provincial Natural Science Foundation of China[LR19H310001] ; Ministry of Science and Technology[2019YFA050880] ; Key R&D Projects of Zhejiang Province[2021C03039] ; Fundamental Research Funds for the Central Universities
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001026236800016
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/306839]  
专题新药研究国家重点实验室
通讯作者Zhang, Shuyang; Zhang, Yan; Xu, H. Eric
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Zhejiang Univ, Dept Biophys, Sch Med, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China
4.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Pathol, Sch Med, Hangzhou, Zhejiang, Peoples R China
5.Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Zhejiang, Peoples R China
6.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Sch Med, Hangzhou, Zhejiang, Peoples R China
7.Zhejiang Prov Key Lab Immun & Inflammatory Dis, Hangzhou, Zhejiang, Peoples R China
8.Peking Union Med Coll & Chinese Acad Med Sci, Dept Cardiol, Peking Union Med Coll Hosp, Beijing, Peoples R China
9.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Med Res Ctr, Beijing, Peoples R China
10.Tsinghua Univ, Sch Med, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Duan, Jia,Xu, Peiyu,Zhang, Huibing,et al. Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor[J]. NATURE COMMUNICATIONS,2023,14(1):12.
APA Duan, Jia.,Xu, Peiyu.,Zhang, Huibing.,Luan, Xiaodong.,Yang, Jiaqi.,...&Xu, H. Eric.(2023).Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor.NATURE COMMUNICATIONS,14(1),12.
MLA Duan, Jia,et al."Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor".NATURE COMMUNICATIONS 14.1(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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