EMD-38095

Single-particle
2.41 Å
EMD-38095 Deposition: 23/11/2023
Map released: 06/03/2024
Last modified: 06/03/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-38095

MRE-269 bound Prostacyclin Receptor G protein complex

EMD-38095

Single-particle
2.41 Å
EMD-38095 Deposition: 23/11/2023
Map released: 06/03/2024
Last modified: 06/03/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: IP-Gs complex
Fitted models: 8x79 (Avg. Q-score: 0.512)

Deposition Authors: Wang JJ , Jin S , Zhang H , Xu Y , Hu W , Jiang Y, Chen C, Wang DW , Xu HE , Wu C
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
(2024) Sci Adv , 10 , eadk5184 - eadk5184
PUBMED: 38335293
DOI: doi:10.1126/sciadv.adk5184
ISSN: 2375-2548
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.