Structural basis of antifolate recognition and transport by PCFT

• Published in: Nature (London) 2021-07, Vol.595 (7865), p.130-134
• Main Authors: Parker, Joanne L., Deme, Justin C., Kuteyi, Gabriel, Wu, Zhiyi, Huo, Jiandong, Goldman, I. David, Owens, Raymond J., Biggin, Philip C., Lea, Susan M., Newstead, Simon
• Format: Article
• Language: English
• Subjects: 631/535/1258/1259; 631/57/2283; 631/67/1059/153; Amino acids; Antifolate agents; Apoproteins - chemistry; Apoproteins - metabolism; Apoproteins - ultrastructure; Binding sites; Biological Transport; Cancer therapies; Cryoelectron Microscopy; Drug delivery; Drugs; Electron microscopy; Folic acid; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - metabolism; Humanities and Social Sciences; Humans; Immunosuppressive agents; Ligands; Microscopy; Models, Molecular; multidisciplinary; Mutation; Nucleic acids; Pemetrexed - chemistry; Pemetrexed - metabolism; Proteins; Proton-Coupled Folate Transporter - chemistry; Proton-Coupled Folate Transporter - metabolism; Proton-Coupled Folate Transporter - ultrastructure; Protons; Recognition; Salt; Science; Science (multidisciplinary); Substrates; Vitamin B; Vitamin deficiency
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03579-z

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S -adenylsmethionine 1 , 2 . Folate deficiency is associated with a number of developmental, immune and neurological disorders 3 – 5 . Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body 3 , 6 . The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus 4 , 7 , and is an important route for the delivery of antifolate drugs in cancer chemotherapy 8 – 10 . How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT. Cryo-electron microscopy structures of PCFT in a substrate-free state and bound to the antifolate drug pemetrexed provide insights into how this protein recognizes folates and mediates their transport into cells.