Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2

doi:10.1073/pnas.2101279118

	Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2
	Wang, Xi 1,2; Cheng, Xi 3,4; Zhao, Lihua 2,5; Wang, Yuzhe 1,2; Ye, Chenyu ; Zou, Xinyu 7; Dai, Antao 1; Cong, Zhaotong 6; Chen, Jian 6; Zhou, Qingtong 8
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2021-08-10
卷号	118 期号:32 页码:8
关键词	parathyroid hormone receptor 2 cryo-electron microscopy G protein-coupled receptor ligand recognition syndromic short stature
ISSN号	0027-8424
DOI	10.1073/pnas.2101279118
通讯作者	Xu, H. Eric(eric.xu@simm.ac.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要	The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 angstrom. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
资助项目	National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[32071203] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-003] ; National Key Basic Research Program of China[2018YFA0507000] ; Ministry of Science and Technology of China[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB37030103] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; Shanghai Science and Technology Development Fund[18ZR1447800] ; Young Innovator Association of Chinese Academy of Science[2018325] ; SA-SIBS Scholarship Program ; Youth Innovation Promotion Association of Chinese Academy of Science[2018319]
WOS关键词	CRYO-EM STRUCTURE ; TUBEROINFUNDIBULAR PEPTIDE ; GLP-1 RECEPTOR ; 39 RESIDUES ; AGONIST ; ACTIVATION ; TIP39 ; DYNAMICS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000685043400013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298088]
专题	中国科学院上海药物研究所
通讯作者	Xu, H. Eric; Yang, Dehua; Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Drug Discovery & Design, Shanghai 201203, Peoples R China 4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 6.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 7.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan 430074, Peoples R China 8.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Wang, Xi,Cheng, Xi,Zhao, Lihua,et al. Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(32):8.
APA	Wang, Xi.,Cheng, Xi.,Zhao, Lihua.,Wang, Yuzhe.,Ye, Chenyu.,...&Wang, Ming-Wei.(2021).Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(32),8.
MLA	Wang, Xi,et al."Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.32(2021):8.