Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor
Shiyi Shen,
Dongxue Wang,
Heng Liu,
Xinheng He,
Yinglong Cao,
Juanhua Chen,
Shujie Li,
Xi Cheng,
H. Eric Xu,
Jia Duan
Affiliations
Shiyi Shen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
Dongxue Wang
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
Heng Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xinheng He
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
Yinglong Cao
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Juanhua Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Shujie Li
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xi Cheng
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
H. Eric Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Jia Duan
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding author
Summary: 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 Gq-coupled receptors, enabling distinct interactions with Gq. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with Gq. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
