Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs

doi:10.1126/sciadv.adk5184

	Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs
	Wang, James Jiqi 1,2; Jin, Sanshan3,4 ; Zhang, Heng 1; Xu, Youwei 1; Hu, Wen 1; Jiang, Yi3,4 ; Chen, Chen 2; Wang, Dao Wen 2; Xu, H. Eric1,4,5 ; Wu, Canrong 1
	2024-02
发表期刊	SCIENCE ADVANCES (IF:11.7[JCR-2023],13.7[5-Year])
ISSN	2375-2548
EISSN	2375-2548
卷号	10 期号:6
发表状态	已发表
DOI	10.1126/sciadv.adk5184
摘要	The prostacyclin (PGI2) receptor (IP) is a Gs-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial hypertension (PAH) and several other diseases. Here we report cryo–electron microscopy (cryo-EM) structures of the human IP-Gs complex bound with two anti-PAH drugs, treprostinil and MRE-269 (active form of selexipag), at global resolutions of 2.56 and 2.41 angstrom, respectively. These structures revealed distinct features governing IP ligand binding, receptor activation, and G protein coupling. Moreover, comparison of the activated IP structures uncovered the mechanism and key residues that determine the superior selectivity of MRE-269 over treprostinil. Combined with molecular docking and functional studies, our structures provide insight into agonist selectivity, ligand recognition, receptor activation, and G protein coupling. Our results provide a structural template for further improving IP-targeting drugs to reduce off-target activation of prostanoid receptors and adverse effects. © 2024 American Association for the Advancement of Science. All rights reserved.
关键词	Blood pressure Chemical activation Proteins Arterial hypertension Blood pressure regulation Coupled receptors Cryo-electron microscopy G protein Inflammatory response Ligand binding Prostacyclin receptors Receptor activation Therapeutic targets
URL	查看原文
收录类别	EI ; SCI
语种	英语
资助项目	CAS Strategic Priority Research Program[XDB37030103] ; National Natural Science Foundation of China["32301016","32130022","82121005","32171187","82330010","81902085"] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; National Key R&D Program of China[2022YFC2703105] ; China Postdoctoral Science Foundation Funded Project[2021M703342] ; Shanghai Post-doctoral Excellence Program[2021429] ; Key tasks of Lingang Laboratory["LG202101-01-03","LG202101-01-640","LG-GG-202204-01"]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001189871700005
出版者	American Association for the Advancement of Science
EI入藏号	20240815574116
EI主题词	Ligands
EI分类号	461.9 Biology ; 801.4 Physical Chemistry ; 802.2 Chemical Reactions ; 804 Chemical Products Generally ; 804.1 Organic Compounds
原始文献类型	Journal article (JA)
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/349969
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_徐华强组生命科学与技术学院_博士生
通讯作者	Wang, Dao Wen; Xu, H. Eric; Wu, Canrong
作者单位	1.State Key laboratory of drug Research, Shanghai institute of Materia Medica, chinese Academy of Sciences, Shanghai; 201203, China; 2.division of cardiology, department of internal Medicine, hubei Key laboratory of Genetics and Molecular Mechanism of cardiologic disorders, tongji hospital, tongji Medical college, huazhong University of Science and technology, Wuhan; 430000, China; 3.lingang laboratory, Shanghai; 200031, China; 4.School of life Science and technology, Shanghaitech University, Shanghai; 201210, China; 5.University of chinese Academy of Sciences, Beijing; 100049, 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, James Jiqi,Jin, Sanshan,Zhang, Heng,et al. Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs[J]. SCIENCE ADVANCES,2024,10(6).
APA	Wang, James Jiqi.,Jin, Sanshan.,Zhang, Heng.,Xu, Youwei.,Hu, Wen.,...&Wu, Canrong.(2024).Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs.SCIENCE ADVANCES,10(6).
MLA	Wang, James Jiqi,et al."Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs".SCIENCE ADVANCES 10.6(2024).