Scientists solved the 3‑D shape of the kisspeptin receptor when it’s bound to its natural peptide (kisspeptin‑10) and a lab‑made version. They saw how the peptide fits into the receptor and discovered the receptor twists in a unique way that makes it talk to a specific G‑protein (Gq). This helps explain how kisspeptin triggers hormone signals that control reproduction.

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° 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.