2. Academic Validation
  3. Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs

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

  • Sci Adv. 2024 Feb 9;10(6):eadk5184. doi: 10.1126/sciadv.adk5184.
James Jiqi Wang 1 2,  Sanshan Jin 3 4,  Heng Zhang 1,  Youwei Xu 1,  Wen Hu 1,  Yi Jiang 3 4,  Chen Chen 2,  Dao Wen Wang 2,  H Eric Xu 1 4 5,  Canrong Wu 1
Affiliations

Affiliations

  • 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.
  • 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.
PMID: 38335293 DOI: 10.1126/sciadv.adk5184
Abstract

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.

Figures
Products