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

ABSTRACT: The prostacyclin (PGI₂) 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. Combine

SUBMITTER: Wang JJ 

PROVIDER: S-EPMC10857463 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature