Structures of full-length glycoprotein hormone receptor signalling complexes

doi:10.1038/s41586-021-03924-2

	Structures of full-length glycoprotein hormone receptor signalling complexes
	Duan, Jia 1,2,3; Xu, Peiyu 1,2,3; Cheng, Xi 2,3; Mao, Chunyou 4,5,6,7,8,14; Croll, Tristan 9; He, Xinheng 1,2,3; Shi, Jingjing 2,3; Luan, Xiaodong 10,11,12; Yin, Wanchao 2,3; You, Erli 2,3
刊名	NATURE
	2021-09-22
页码	24
ISSN号	0028-0836
DOI	10.1038/s41586-021-03924-2
通讯作者	Zhang, Yan(zhang_yan@zju.edu.cn) ; Jiang, Yi(yijiang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要	Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone(1,2). Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs(3-6). They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain(3). Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G(s)), and one of the structures also contains Org43553, an allosteric agonist(7). The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.
资助项目	Ministry of Science and Technology (China)[2018YFA0507002] ; Ministry of Science and Technology (China)[2019YFA0508800] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB08020303] ; National Natural Science Foundation of China[31770796] ; National Natural Science Foundation of China[81922071] ; National Science and Technology Major Project 'Key New Drug Creation and Manufacturing Program'[2018ZX09711002] ; Wellcome Trust[209407/Z/17/Z] ; National Key R&D Program of China[2020YFC0861000] ; CAMS Innovation Fund for Medical Sciences[2020-I2M-CoV19-001] ; Tsinghua University-Peking University Center for Life Sciences[045-160321001] ; Science and Technology Commission of Shanghai Municipal[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05] ; Shanghai Sailing Program[19YF1457600] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University ; Youth Innovation Promotion Association of Chinese Academy of Science[2018319]
WOS关键词	FOLLICLE-STIMULATING-HORMONE ; MOLECULAR-DYNAMICS SIMULATIONS ; AGONIST ; GONADOTROPIN ; ACTIVATION ; ECTODOMAIN ; RESOLUTION ; BIOLOGY
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PORTFOLIO
WOS记录号	WOS:000698366900010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297900]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Yan; Jiang, Yi; Xu, H. Eric
作者单位	1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 4.Zhejiang Univ, Dept Biophys, Sch Med, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China 5.Zhejiang Univ, Dept Pathol, Sch Med, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China 6.Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Peoples R China 7.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Sch Med, Hangzhou, Peoples R China 8.Zheijang Prov Key Lab Immun & Inflammatory Dis, Hangzhou, Peoples R China 9.Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge, England 10.Tsinghua Univ, Sch Med, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Duan, Jia,Xu, Peiyu,Cheng, Xi,et al. Structures of full-length glycoprotein hormone receptor signalling complexes[J]. NATURE,2021:24.
APA	Duan, Jia.,Xu, Peiyu.,Cheng, Xi.,Mao, Chunyou.,Croll, Tristan.,...&Xu, H. Eric.(2021).Structures of full-length glycoprotein hormone receptor signalling complexes.NATURE,24.
MLA	Duan, Jia,et al."Structures of full-length glycoprotein hormone receptor signalling complexes".NATURE (2021):24.