The solute carrier protein SLC19A1, also known as the reduced folate carrier, plays a crucial role in transporting folate and antifolate drugs, which are essential in cancer treatment.

Folate is vital for mammalian growth and development, serving as a one-carbon unit donor in various metabolic processes.

Recent advancements in cryo-electron microscopy have revealed that SLC19A1 adopts an outward-open conformation, which is critical for its substrate binding and transport.

The structure of SLC19A1 bound to 5-methyltetrahydrofolate (5-MTHF) and methotrexate (MTX) has been elucidated, providing insights into the interactions at the binding site.

PT523, an atypical antifolate, has been shown to preferentially bind to SLC19A1, enhancing transport efficacy compared to conventional antifolates due to additional interactions.

In addition to folate, recent studies have identified SLC19A1's novel role in transporting cyclic dinucleotides (CDNs), which are important immune signaling molecules.

Mutagenesis studies, including the G307F mutation, have demonstrated how conformational changes in SLC19A1 affect its function and substrate recognition.

SLC19A1 consists of 12 transmembrane helices and operates through a rocker-switch mechanism to facilitate the transport of substrates across cell membranes.

These findings not only enhance the understanding of SLC19A1's transport cycle but also pave the way for developing selective antifolate drugs and targeting folate transport in tumors.

The study also revealed the binding dynamics of CDN monomers in SLC19A1, indicating the need for further structural investigations to confirm the transport mechanisms.