7BC7

Cryo-EM structure of the proton coupled folate transporter at pH 6.0 bound to pemetrexed

Summary for 7BC7

• Entry DOI: 10.2210/pdb7bc7/pdb
• EMDB information: 12141
• Descriptor: Proton-coupled folate transporter, nanobody, 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID (3 entities in total)
• Functional Keywords: transporter folate proton symporter, membrane protein
• Biological source: Gallus gallus (Chicken); More
• Total number of polymer chains: 2
• Total formula weight: 65253.99

Authors

Parker, J.L.,Deme, J.C.,Lea, S.M.,Newstead, S. (deposition date: 2020-12-18, release date: 2021-05-12, Last modification date: 2025-07-02)

Primary citation

Parker, J.L.,Deme, J.C.,Kuteyi, G.,Wu, Z.,Huo, J.,Goldman, I.D.,Owens, R.J.,Biggin, P.C.,Lea, S.M.,Newstead, S.
Structural basis of antifolate recognition and transport by PCFT.
Nature, 595:130-134, 2021

PubMed Abstract: 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. Folate deficiency is associated with a number of developmental, immune and neurological disorders. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus, and is an important route for the delivery of antifolate drugs in cancer chemotherapy. 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.

PubMed: 34040256
DOI: 10.1038/s41586-021-03579-z

Experimental method

ELECTRON MICROSCOPY (3.3 Å)