9JRT

Structural Insights into Selective Antagonism of TG6-129 and EP2 Prostaglandin Receptor

これはPDB形式変換不可エントリーです。

9JRT の概要

• エントリーDOI: 10.2210/pdb9jrt/pdb
• EMDBエントリー: 61763
• 分子名称: GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562, Heavy chain of Fab fragment, Nb, ... (5 entities in total)
• 機能のキーワード: gpcr, membrane protein/immune system, membrane protein-immune system complex
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 137999.59

構造登録者

Wu, Y.L.,Zhang, H.,Xu, J.Y.,Wu, C.R.,Xu, E.H. (登録日: 2024-09-29, 公開日: 2025-10-22, 最終更新日: 2025-12-17)

主引用文献

Wu, Y.,Zhang, H.,Xu, J.,Wu, K.,Hu, W.,He, X.,Wang, G.,Wu, C.,Xu, H.E.
Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors.
Embo J., 44:7242-7262, 2025

PubMed Abstract: Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors is crucial in regulating inflammation, pain, and cancer progression. While selective and dual antagonists for these receptors hold therapeutic potential, their binding mechanisms and selectivity have remained unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, as well as with the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that dictate antagonist selectivity and efficacy. Notably, TG6-129 displays a novel binding mode, engaging deeply with EP2 while interacting more superficially with EP4 in a two-warhead manner. Furthermore, comparisons of active and inactive receptor structures elucidate the mechanisms underlying EP2 activation and antagonism. Overall, these findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors.

PubMed: 41162752
DOI: 10.1038/s44318-025-00611-0

実験手法

ELECTRON MICROSCOPY (3.28 Å)