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Publication Abstract from PubMed

The prostacyclin (PGI(2)) receptor (IP) is a G(s)-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-G(s) 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.

Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs.,Wang JJ, Jin S, Zhang H, Xu Y, Hu W, Jiang Y, Chen C, Wang DW, Xu HE, Wu C Sci Adv. 2024 Feb 9;10(6):eadk5184. doi: 10.1126/sciadv.adk5184. Epub 2024 Feb 9. PMID:38335293^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.