8XZI

Cryo-EM structure of the CMF-019-bound human APLNR-Gi complex

This is a non-PDB format compatible entry.

Summary for 8XZI

• Entry DOI: 10.2210/pdb8xzi/pdb
• EMDB information: 38797
• Descriptor: Apelin receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: aplnr, cmf-019, class a gpcr, g-protein-biased small molecule agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 155323.45

Authors

Wang, W.,Ji, S.,Zhang, Y. (deposition date: 2024-01-21, release date: 2024-03-20, Last modification date: 2025-07-23)

Primary citation

Wang, W.W.,Ji, S.Y.,Zhang, W.,Zhang, J.,Cai, C.,Hu, R.,Zang, S.K.,Miao, L.,Xu, H.,Chen, L.N.,Yang, Z.,Guo, J.,Qin, J.,Shen, D.D.,Liang, P.,Zhang, Y.,Zhang, Y.
Structure-based design of non-hypertrophic apelin receptor modulator.
Cell, 187:1460-1475.e20, 2024

PubMed Abstract: Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

PubMed: 38428423
DOI: 10.1016/j.cell.2024.02.004

Experimental method

ELECTRON MICROSCOPY (2.7 Å)