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 and 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.内科学系大内科心血管内科华中科技大学同济医学院附属同济医院内科门诊[3]Lingang laboratory, Shanghai 200031, China.[4]School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.[5]University of Chinese Academy of Sciences, Beijing 100049, China.
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.
基金：
This
work was partially supported by CAS Strategic Priority Research Program (XDB37030103 to H.E.X.);
The National Natural Science Foundation of China (32301016 to C.W., 32130022 to H.E.X.,
82121005 to H.E.X., 32171187 to Y.J., 82121005 to Y.J., 82330010 to D.W.W., 81902085 to Y.X.);
Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to H.E.X.); the
National Key R&D Program of China (2022YFC2703105 to H.E.X.); China Postdoctoral Science
Foundation Funded Project (2021M703342 to C.W.); Shanghai Post-doctoral Excellence Program
(2021429 to C.W.); Key tasks of Lingang Laboratory (LG202101-01-03 to Y.X., LG202101-01-640 to
Y.J.); Grant No. LG-GG-202204-01 (Y.J. and H.E.X.)
第一作者单位：[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 and 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.
通讯作者：
通讯机构：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.[4]School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.[5]University of Chinese Academy of Sciences, Beijing 100049, China.
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):eadk5184.doi:10.1126/sciadv.adk5184.
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):eadk5184
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