8X79

MRE-269 bound Prostacyclin Receptor G protein complex

Summary for 8X79

• Entry DOI: 10.2210/pdb8x79/pdb
• EMDB information: 38095
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,GNAS complex locus,GNAS complex locus, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: agonist, complex, lipid receptor, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 131666.97

Authors

Wang, J.J.,Jin, S.,Zhang, H.,Xu, Y.,Hu, W.,Jiang, Y.,Chen, C.,Wang, D.W.,Xu, H.E.,Wu, C. (deposition date: 2023-11-23, release date: 2024-03-06)

Primary citation

Wang, J.J.,Jin, S.,Zhang, H.,Xu, Y.,Hu, W.,Jiang, Y.,Chen, C.,Wang, D.W.,Xu, H.E.,Wu, C.
Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs.
Sci Adv, 10:eadk5184-eadk5184, 2024

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 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.

PubMed: 38335293
DOI: 10.1126/sciadv.adk5184

Experimental method

ELECTRON MICROSCOPY (2.41 Å)