8XZF

Cryo-EM structure of the WN561-bound human APLNR-Gi complex

8XZF の概要

• エントリーDOI: 10.2210/pdb8xzf/pdb
• EMDBエントリー: 38794
• 分子名称: 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)
• 機能のキーワード: aplnr, class a gpcr, synthetic peptide, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 156470.83

構造登録者

Wang, W.,Ji, S.,Zhang, Y. (登録日: 2024-01-21, 公開日: 2024-03-20, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3 Å)