EMD-38095
MRE-269 bound Prostacyclin Receptor G protein complex
EMD-38095
Single-particle2.41 Å
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Map released: 06/03/2024
Last modified: 06/03/2024
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
Sample: IP-Gs complex
Fitted models: 8x79 (Avg. Q-score: 0.512)
Deposition Authors: Wang JJ
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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
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(2024) Sci Adv , 10 , eadk5184 - eadk5184
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.
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.