8ZJE

Cryo-EM structure of kisspeptin receptor bound to TAK-448

8ZJE の概要

• エントリーDOI: 10.2210/pdb8zje/pdb
• EMDBエントリー: 60142
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: cryo-em, kisspeptin receptor, gpr54, g proteins, membrane protein, kiss1r
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 158151.18

構造登録者

Shen, S.,Liu, H.,Xu, H.E. (登録日: 2024-05-14, 公開日: 2024-07-03, 最終更新日: 2025-01-15)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.07 Å)