Structural basis of antifolate recognition and transport by PCFT

Joanne L. Parker (), Justin C. Deme, Gabriel Kuteyi, Zhiyi Wu, Jiandong Huo, I. David Goldman, Raymond J. Owens, Philip C. Biggin, Susan M. Lea () and Simon Newstead ()
Additional contact information
Joanne L. Parker: University of Oxford
Justin C. Deme: University of Oxford
Gabriel Kuteyi: University of Oxford
Zhiyi Wu: University of Oxford
Jiandong Huo: The Rosalind Franklin Institute
I. David Goldman: Albert Einstein College of Medicine
Raymond J. Owens: The Rosalind Franklin Institute
Philip C. Biggin: University of Oxford
Susan M. Lea: University of Oxford
Simon Newstead: University of Oxford

Nature, 2021, vol. 595, issue 7865, 130-134

Abstract: 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-adenylsmethionine1,2. Folate deficiency is associated with a number of developmental, immune and neurological disorders3–5. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body3,6. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus4,7, and is an important route for the delivery of antifolate drugs in cancer chemotherapy8–10. 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03579-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:595:y:2021:i:7865:d:10.1038_s41586-021-03579-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03579-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().