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; Xia, Tian 7; Jiang, Hualiang 2,3; Xu, H. Eric 2,5; Yang, Dehua 1,2,5; Wang, Ming-Wei1,2,5,6,8,9
	2021-08-10
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	0027-8424
卷号	118 期号:32
DOI	10.1073/pnas.2101279118
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.
关键词	parathyroid hormone receptor 2 cryo-electron microscopy G protein-coupled receptor ligand recognition syndromic short stature
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收录类别	SCIE
语种	英语
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000685043400013
出版者	NATL ACAD SCIENCES
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127926
专题	生命科学与技术学院_特聘教授组_王明伟组
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
通讯作者单位	生命科学与技术学院
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).
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).
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).