8ZJD

Cryo-EM structure of kisspeptin receptor bound to KP-10

Summary for 8ZJD

• Entry DOI: 10.2210/pdb8zjd/pdb
• EMDB information: 60141
• Descriptor: KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor, G-protein coupled receptor 54, GPR54, KISS1R, kisspeptin-10, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: cryo-em, kisspeptin receptor, gpr54, kiss1r, g proteins, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 171525.19

Authors

Shen, S.,Liu, H.,Xu, H.E. (deposition date: 2024-05-14, release date: 2024-07-03, Last modification date: 2025-01-15)

Primary citation

Shen, S.,Wang, D.,Liu, H.,He, X.,Cao, Y.,Chen, J.,Li, S.,Cheng, X.,Xu, H.E.,Duan, J.
Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor.
Cell Rep, 43:114389-114389, 2024

PubMed 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 other G-coupled receptors, enabling distinct interactions with G. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.

PubMed: 38935498
DOI: 10.1016/j.celrep.2024.114389

Experimental method

ELECTRON MICROSCOPY (3.06 Å)