上海科技大学知识管理系统

Kisspeptin signaling through its G protein -coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic -pituitary -gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40 degrees angular deviation in its intracellular TM6 region compared to other G q -coupled receptors, enabling distinct interactions with G q . This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G q . Our findings pave the way for structure -guided design of therapeutics targeting this physiologically indispensable receptor.