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Title | Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs. |
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Journal, issue, pages | Sci Adv, Vol. 10, Issue 6, Page eadk5184, Year 2024 |
Publish date | Feb 9, 2024 |
Authors | James Jiqi Wang / Sanshan Jin / Heng Zhang / Youwei Xu / Wen Hu / Yi Jiang / Chen Chen / Dao Wen Wang / H Eric Xu / Canrong Wu / |
PubMed Abstract | The prostacyclin (PGI) receptor (IP) is a G-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial ...The prostacyclin (PGI) receptor (IP) is a G-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 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. |
External links | Sci Adv / PubMed:38335293 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.41 - 2.56 Å |
Structure data | EMDB-38095, PDB-8x79: EMDB-38096, PDB-8x7a: |
Chemicals |
ChemComp-Y9Q:
ChemComp-Y9J: |
Source |
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Keywords | SIGNALING PROTEIN / Agonist / Complex / lipid receptor |