# Structural basis for prostaglandin and drug transport via SLCO2A1

## TL;DR

This study reveals how SLCO2A1 transporter recognizes and transports prostaglandins and drugs, offering insights into drug and metabolite transport mechanisms.

## Contribution

The study provides cryogenic electron microscopy structures and molecular dynamics of SLCO2A1 bound to prostaglandins and drugs, revealing substrate recognition mechanisms.

## Key findings

- Cryo-EM structures of SLCO2A1 bound to prostaglandins and four drugs were determined.
- Molecular dynamics and cellular assays explain how SLCO2A1 recognizes and transports substrates.
- The study identifies mechanistic details of substrate selection in the SLCO superfamily.

## Abstract

Organic anion-transporting polypeptide transporters (SLCO/OATPs) function as cellular gatekeepers, regulating intestinal absorption, hepatic and renal clearance, and the tissue distribution of drugs and metabolites in the human body. However, the mechanisms underlying substrate selection within the SLCO superfamily remain unclear, hampering efforts to rationalize the interaction of drugs and metabolites with these transporters. SLCO2A1 (also known as OATP2A1) is responsible for the distribution of eicosanoids, including prostaglandins (PGs) and thromboxanes, throughout the body, in addition to several families of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, we present cryogenic electron microscopy structures of SLCO2A1 bound to endogenous PGs and to four widely prescribed medications for treating inflammation, chronic asthma, and Parkinson’s disease (PD). Complementary molecular dynamics and in vivo cellular assays elucidate the molecular basis for PG and drug recognition. Our study reports essential mechanistic details that underpin substrate selection and subfamily adaptation within the broader SLCO superfamily of drug and metabolite transporters.

SLCO2A1 (also known as OATP2A1) is responsible for the transport of eicosanoids, including prostaglandins (PGs), as well as of a subset of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, structures of SLCO2A1 bound to PGs and to four widely used drugs elucidate the molecular basis for PG and drug recognition.