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

作者：James Jiqi Wang, Sanshan Jin, Heng Zhang, Youwei Xu, Wen Hu, Yi Jiang, Chen Chen, Dao Wen Wang, H. Eric Xu, Canrong Wu · 发表于：Science Advances · 年份：2024 · DOI：10.1126/sciadv.adk5184 · 研究领域：Pulmonary Hypertension Research and Treatments、Receptor Mechanisms and Signaling、Hormonal Regulation and Hypertension

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.