Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38335293.
- Also identified by DOI 10.1126/sciadv.adk5184 and PMC identifier 10857463.
- Licence recorded as CC BY-NC.
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Abstract
The prostacyclin (PGI<sub>2</sub>) receptor (IP) is a G<sub>s</sub>-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<sub>s</sub> 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.
Medical subject headings
- Acetates
- Antihypertensive Agents
- GTP-Binding Proteins
- Pyrazines