EMD-38970
The low resolution consensus map of the MM07 bound APLNR-Gi1 structure.
EMD-38970
Single-particle2.5 Å
Deposition: 01/02/2024Map released: 20/03/2024
Last modified: 16/10/2024
Sample Organism:
Homo sapiens
Sample: MM07 bound APLNR complex.
Deposition Authors: Wang W, Ji S, Zhang Y
Sample: MM07 bound APLNR complex.
Deposition Authors: Wang W, Ji S, Zhang Y
Structure-based design of non-hypertrophic apelin receptor modulator.
Wang WW,
Ji SY,
Zhang W,
Zhang J,
Cai C,
Hu R,
Zang SK,
Miao L,
Xu H,
Chen LN,
Yang Z,
Guo J,
Qin J,
Shen DD,
Liang P,
Zhang Y,
Zhang Y
(2024) Cell , 187 , 1460 - 1475.e20
(2024) Cell , 187 , 1460 - 1475.e20
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-Gi1 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.
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-Gi1 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.