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Hormone- and antibody-mediated activation of the thyrotropin receptor

文献类型：期刊论文

作者Duan, Jia10,11; Xu, Peiyu1,11; Luan, Xiaodong6,7,8,9; Ji, Yujie10,11; He, Xinheng5,10,11; Song, Ning4,10; Yuan, Qingning11; Jin, Ye8,9; Cheng, Xi5; Jiang, Hualiang3,5,10
刊名NATURE
出版日期2022-08-08
页码26
ISSN号0028-0836
DOI10.1038/s41586-022-05173-3
通讯作者Zhang, Shuyang(shuyangzhang103@nrdrs.org) ; Jiang, Yi(yjiang@lglab.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone(1-3). Aberrant signalling of TSHR by autoantibodies causes Graves' disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide(4). Here we report the active structures of TSHR with TSH and the activating autoantibody M22(5), both bound to the allosteric agonist ML-109(6), as well as an inactivated TSHR structure with the inhibitory antibody K1-70(7). Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain(8). One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts(9). These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves' disease.
WOS关键词TSH RECEPTOR ; CRYSTAL-STRUCTURE ; STIMULATING-HORMONE ; GLYCOPROTEIN HORMONES ; EXTRACELLULAR DOMAIN ; GRAVES-DISEASE ; ECTODOMAIN ; PROTEINS ; BLOCKING ; CLEAVAGE
资助项目Ministry of Science and Technology (China)[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project ; 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] ; 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]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000852585100002
源URL[http://119.78.100.183/handle/2S10ELR8/302398]  
专题新药研究国家重点实验室
通讯作者Zhang, Shuyang; Jiang, Yi; Xu, H. Eric
作者单位1.MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
2.Lingang Lab, Shanghai, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
4.Chinese Acad Sci, Ctr Immunol Dis, Shanghai Inst Mat Med, Shanghai, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
6.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing, Peoples R China
7.Tsinghua Univ, Sch Med, Beijing, Peoples R China
8.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Med Res Ctr, Beijing, Peoples R China
9.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Cardiol, Beijing, Peoples R China
10.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Duan, Jia,Xu, Peiyu,Luan, Xiaodong,et al. Hormone- and antibody-mediated activation of the thyrotropin receptor[J]. NATURE,2022:26.
APA Duan, Jia.,Xu, Peiyu.,Luan, Xiaodong.,Ji, Yujie.,He, Xinheng.,...&Xu, H. Eric.(2022).Hormone- and antibody-mediated activation of the thyrotropin receptor.NATURE,26.
MLA Duan, Jia,et al."Hormone- and antibody-mediated activation of the thyrotropin receptor".NATURE (2022):26.

入库方式： OAI收割

来源：上海药物研究所

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