Molecular basis of prostaglandin E₂ reuptake by organic anion transporter PGT.

Abstract

Prostaglandins (PGs) are bioactive lipids that regulate inflammation, reproduction, and vasopermeability. Timely clearance of excessive PGs is critical to prevent potential damages caused by prolonged signalling. The high-affinity prostaglandin transporter (PGT) plays an essential role in this termination process by efficiently re-uptaking PGs into cells. Here, we report human PGT structures in different oligomerization and substrate-binding states. Beyond the canonical MFS-fold, PGT harbours a cystine-rich extracellular segment that incorporates a Kazal-like domain crucial for PGT localization and activity. Two distinct PGE₂-bound structures revealed essential elements for substrate recognition, elucidating a PGE₂-flipping process during the multi-stop translocation cycle. Notably, our data suggest that PGT may dimerize in detergent micelles and lipid nanodiscs. This dimerization would likely increase the mobility of the extracellular region and induces a profound rotation of the C-domain transmembrane helices, an interesting observation for MFS transporters. These functionally distinct snapshots thus shed light on prostaglandin clearance and reveal intriguing features of MFS transporters.