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Structure-based Design of Non-hypertrophic Apelin Receptor Modulator by Wei-Wei Wang & Su-Yu Ji & Wenjia Zhang & Junxia Zhang & Chenxi Cai & Rubi Hu & Shao-Kun Zang & Luwei Miao & Haomang Xu & Li-Nan Chen & Zongkuai Yang & Jia Guo & Jiao Qin & Dan-Dan Shen & Ping Liang & Yan Zhang is a book available to read on EtoBox.

What is Structure-based Design of Non-hypertrophic Apelin Receptor Modulator about?

Cell, Corrected proof. doi:10.1016/j.cell.2024.02.004SUMMARYApelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which isregarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through theb-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 withfunctional 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 ofWN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adoptthe 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 ofnext-generation cardiovascular medications.

Author

Wei-Wei Wang & Su-Yu Ji & Wenjia Zhang & Junxia Zhang & Chenxi Cai & Rubi Hu & Shao-Kun Zang & Luwei Miao & Haomang Xu & Li-Nan Chen & Zongkuai Yang & Jia Guo & Jiao Qin & Dan-Dan Shen & Ping Liang & Yan Zhang

Publisher

x

Published

2024

Language

EN