The prostaglandin transporter (PGT) is a member of the OATP family of membrane transporters. PGT mediates the uptake of prostaglandins from the extracellular environment to enable intracellular enzymatic degradation and termination of signaling. In addition to importing prostaglandins, PGT is also an essential core component of the Maxi-Cl channel, which facilitates cellular release of ATP and other small organic anions. Despite progress on understanding the (patho) physiological roles of PGT and development of small molecules to inhibit this transporter, molecular details of the overall structure and transport mechanism remain elusive. In this study, we report the cryo-EM structure of human PGT, revealing an overall topology consistent with other OATPs despite possessing dual transporter/channel functionality. We additionally investigated the role of disulfide bonds in the cysteine-rich extracellular domain. We demonstrate that intra-loop disulfide bonds are essential for proper N-glycosylation, plasma membrane trafficking, and prostaglandin import activity. In contrast, inter-loop disulfides restricted maximal prostaglandin uptake, suggesting a possible regulatory role in modulating PGT activity. Together, these findings uncover new mechanisms of transporter regulation and open opportunities for developing therapeutic strategies targeting prostaglandin signaling.
Yu et al. (Sun,) studied this question.