Structural Insights into Selective and Dual Antagonism of EP2 and EP4 Prostaglandin Receptors

Abstract

Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors plays a crucial role in inflammation, pain, and cancer progression. Selective and dual antagonists of these receptors have shown promising therapeutic potential. However, the structural basis for their binding modes and selectivity remained unclear. Here, we present cryo-EM structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, respectively, as well as the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that govern antagonist selectivity and efficacy. Combining the structural data and functional studies, we uncover the key residues and structural features that differentiate EP2 and EP4 binding sites, including a unique {pi}-{pi} stacking interaction in EP2 and variations in pocket shape and charge distribution. The dual antagonist TG6-129 exhibited a novel binding mode, interacting deeply with EP2 but only shallowly with EP4 in a two-warhead manner. 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.