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Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor

Cell Rep. 2024-06; 
Shiyi Shen, Dongxue Wang, Heng Liu, Xinheng He, Yinglong Cao, Juanhua Chen, Shujie Li, Xi Cheng, H Eric Xu, Jia Duan
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Abstract

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 oth... More

Keywords

CP: Molecular biology, GPCR, Gq, Hormone, KISS1R, Kisspeptin, TAK-448, structure